CN1630641A - Farnesyl protein transferase inhibitors as antitumor agents - Google Patents

Farnesyl protein transferase inhibitors as antitumor agents Download PDF

Info

Publication number
CN1630641A
CN1630641A CNA038047209A CN03804720A CN1630641A CN 1630641 A CN1630641 A CN 1630641A CN A038047209 A CNA038047209 A CN A038047209A CN 03804720 A CN03804720 A CN 03804720A CN 1630641 A CN1630641 A CN 1630641A
Authority
CN
China
Prior art keywords
alkyl
group
substituted
substituting group
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA038047209A
Other languages
Chinese (zh)
Other versions
CN100537542C (en
Inventor
H·Y·朱
F·G·恩乔洛吉
A·B·库珀
T·J·古兹
D·F·拉恩
K·P·米诺尔
R·J·多尔
V·M·吉利加法拉布汗
B·圣珊纳
P·A·平托
B·维布尔巴汉
K·M·基尔堤卡
C·S·阿尔瓦雷兹
J·J·包德温
李格
黄家育
R·A·詹姆士
W·R·比肖普
J·J·-S·王
J·A·德塞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacopeia Drug Discovery Inc
Merck Sharp and Dohme Corp
Original Assignee
Pharmacopeia LLC
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/085,896 external-priority patent/US20030229099A1/en
Application filed by Pharmacopeia LLC, Schering Corp filed Critical Pharmacopeia LLC
Publication of CN1630641A publication Critical patent/CN1630641A/en
Application granted granted Critical
Publication of CN100537542C publication Critical patent/CN100537542C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

Disclosed are novel tricyclic compounds represented by the formula (1.0): and a pharmaceutically acceptable salt or solvate thereof. The compounds are useful for inhibiting farnesyl protein transferase. Also disclosed are pharmaceutical compositions comprising compounds of formula 1.0. Also disclosed are methods of treating cancer using the compounds of formula 1.0.

Description

Farnesyl protein transferase inhibitors as antineoplastic agent
Background of invention
The WO97/23478 that the WO95/10516 that announce April 20 nineteen ninety-five and on July 3rd, 1997 are announced discloses the tricyclic compound that can be used for suppressing farnesyl protein transferase.
On December 10th, 1998, the WO98/54966 of bulletin disclosed the treatment method for cancer, its mode is to use at least two kinds of therapeutical agents, being selected from is the compound of antineoplastic agent, with the compound that is the inhibitor (for example farnesyl protein transferase inhibitors) of isopentene group-protein transferase.
Farnesyl protein transferase (FPT) inhibitor is as known in the art, consults for example U.S.5 of promulgation on February 23rd, 1999,874,442.By co-administered fpt inhibitor and antineoplastic agent and/or radiotherapy, also be known with the method for treatment proliferative disease (for example cancer), consult the U.S.6 that issued on August 1st, 2000 for example, 096,757.
People such as Shih, " farnesyl protein transferase inhibitors SCH66336; in vitro; can and taxanes produce synergism; and strengthen its anti-tumor activity in vivo ", CancerChemother Pharmacol (2000) 46:387-393 discloses SCH66336 and taxol, and the combination of SCH66336 and docetaxel is for the research of some cancerous cell line.
The WO01/45740 that announces June 28 calendar year 2001 discloses the method for a kind of treatment cancer (mammary cancer), and it comprises uses selective estrogen receptor modulators (SERM) and at least a farnesyl tranfering enzyme inhibitor (FTI).The FTI of FTI-277 for mentioning for example.
The website Http:// www.osip.com/press/pr/07-25-01The publication of OSI medicine is disclosed.This publication declaration III clinical trial phase initial, assessment unite utilize egf inhibitor Tarceva (TM) (OSI-774) with carboplatin (Paraplatin _) and taxol (Taxol _), be used for the treatment of nonsmall-cell lung cancer.
The website Http:// cancertrials.nci.nih.gov/types/lung/iressa 12100.htmlIn the disclosure that 12/14/00 includes, disclose followingly about making progress the open clinical trial of (IIIB and IV phase) nonsmall-cell lung cancer, derive from the clinical testing data storehouse of NCI:
(1) gemcitabine and the cis-platinum of ZD1839 (IRESSA, egf inhibitor) and coupling with it, the III phase random research in the pure chemistry therapy patient who suffers from IIIB or IV phase nonsmall-cell lung cancer; With
(2) taxol and the carboplatin of ZD1839 (IRESSA, egf inhibitor) and coupling with it, the III phase random research in the pure chemistry therapy patient who suffers from IIIB or IV phase nonsmall-cell lung cancer.
The WO01/56552 that announces August 9 calendar year 2001 discloses and has utilized fpt inhibitor to be used for the treatment of the pharmaceutical composition that develops mammary cancer with preparation.This fpt inhibitor can be used for developing the other treatment of mammary cancer with one or more, especially increta therapy, for example estrogen antagonist agent, such as estrogen receptor antagon (for example tamoxifen) or selective estrogen receptor modulators or aromatase inhibitor are united use.Adoptable other antiviral agents comprise especially iridium-platinum complex (such as cis-platinum or carboplatin), taxanes (such as taxol or docetaxel), antitumor nucleoside derivates (such as gemcitabine (gemcitabine)) and HER2 antibody (such as trastuzumab).
The WO01/62234 of August 30 calendar year 2001 bulletin discloses a kind of methods of treatment for the treatment of mammal tumor and has made usage with taking medicine, and its mode is the discontinuous administration of farnesyl tranfering enzyme inhibitor, goes through the table one to five day medicine time of shortening.Disclosed is a kind of taking method, wherein farnesyl protein transferase inhibitors be during one to five day in administration, then do not treat at least two weeks.It discloses, and formerly in the research, when when every day, showed administration twice medicine time, farnesyl protein transferase inhibitors has been proved the growth that can suppress mammal tumor.It further discloses, and farnesyl protein transferase inhibitors with single dose administration every day, was gone through one to five day, and the remarkable inhibition that can produce tumor growth continues at least 21 days.It also discloses FTI can unite use with one or more other carcinostatic agents, such as iridium-platinum complex (for example cis-platinum or carboplatin), taxane compounds (for example taxol or docetaxel), antitumor nucleoside derivates (for example gemcitabine), HER2 antibody (for example trastuzumab) and estrogen receptor antagon, or selective estrogen receptor modulators (for example tamoxifen).
The WO01/64199 that announces September 7 calendar year 2001 discloses the combination of specific fpt inhibitor and taxane compounds (for example taxol or docetaxel), can be used for treating cancer.
In view of the present importance on farnesyl protein transferase inhibitors, be the compound that can be used for suppressing farnesyl protein transferase to the welcome contribution of this area.This kind contribution is by the invention provides.
Summary of the invention
The invention provides the compound that can be used for suppressing farnesyl protein transferase (FPT).Fpt inhibitor compound of the present invention is represented with following formula:
Or its pharmacy acceptable salt or solvate, wherein:
Expression N or N one of among a, b, c and the d +O -, and all the other a, b, c and d group are represented carbon, wherein each carbon has the R that is combined on this carbon 1Or R 2Group; Or
Each a, b, c and d are carbon, and wherein each carbon has the R that is combined on this carbon 1Or R 2Group;
Dotted line (---) the optional key of expression;
When this optional key (to C11) when not existing, X represents N or CH, and when this key (to C11) of choosing wantonly when existing, X represents C;
When having optional key (meaning promptly has two keys between C-5 and C-6) between carbon atom 5 (meaning is C-5) and the carbon atom 6 (meaning is C-6), then have only an A substituting group to be combined on the C-5, and have only a B substituting group to be combined on the C-6, and A or B are not H;
When not having optional key (meaning promptly has a singly-bound between C-5 and C-6) between carbon atom 5 and the carbon atom 6, then there are two A substituting groups to be combined on the C-5, wherein each A substituting group is independent the selection, and two B substituting groups are combined on the C-6, wherein each B substituting group is independent the selection, and wherein have at least in two A substituting groups and have at least to be a H in one or two B substituting group, have one in one or two B substituting group at least (meaning is not promptly when having a singly-bound between C-5 and C-6 for H and wherein have at least in two A substituting groups, four substituting group (A, A, B and B) in one of be H, and one is not H);
A and B are independently selected from:
(1)-H；
(2)-R 9；
(3)-R 9-C(O)-R 9；
(4)-R 9-CO 2-R 9a；
(5)-(CH 2) pR 26；
(6)-C (O) N (R 9) 2, each R wherein 9Identical or different;
(7)-C(O)NHR 9；
(8)-C(O)NH-CH 2-C(O)-NH 2；
(9)-C(O)NHR 26；
(10)-(CH 2) pC(R 9)-O-R 9a；
(11)-(CH 2) P-1CH (R 9) 2, its condition is that p is not 0, and each R wherein 9Identical or different;
(12)-(CH 2) pC(O)R 9；
(13)-(CH 2) pC(O)R 27a；
(14)-(CH 2) pC (O) N (R 9) 2, each R wherein 9Identical or different;
(15)-(CH 2) pC(O)NH(R 9)；
(16)-(CH 2) pC (O) N (R 26) 2, each R wherein 26Identical or different;
(17)-(CH 2) pN (R 9)-R 9a, (for example-CH 2-N (CH 2-pyridine)-CH 2-imidazoles);
(18)-(CH 2) pN (R 26) 2, R wherein 26Identical or different (for example-(CH 2) p-NH-CH 2-CH 3);
(19)-(CH 2) pNHC(O)R 50；
(20)-(CH 2) pNHC(O) 2R 50；
(21)-(CH 2) pN (C (O) R 27a) 2, each R wherein 27aIdentical or different;
(22)-(CH 2) pNR 51C(O)R 27；
(23)-(CH 2) pNR 51C (O) R 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms:
(24)-(CH 2) pNR 51C(O)NR 27；
(25)-(CH 2) pNR 51C (O) NR 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(26)-(CH 2) pNR 51C (O) N (R 27a) 2, each R wherein 27aIdentical or different;
(27)-(CH 2) pNHSO 2N (R 51) 2, each R wherein 51Identical or different;
(28)-(CH 2) pNHCO 2R 50；
(29)-(CH 2) pNC(O)NHR 51；
(30)-(CH 2) pCO 2R 51；
(31)-NHR 9；
(32)
Figure A0380472001031
R wherein 30With R 31Identical or different, and each p is independent the selection; Its condition is, to each
Group is worked as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl (for example phenyl) and aralkyl (for example benzyl);
(33)
R wherein 30, R 31, R 32And R 33Identical or different; Its condition is to work as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl (for example phenyl) and aralkyl (for example benzyl); And its condition is to work as R 32Or R 33In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 32Or R 33Be selected from: H, alkyl, aryl (for example phenyl) and aralkyl (for example benzyl);
(34)-thiazolinyl-CO 2R 9a
(35)-thiazolinyl-C (O) R 9a
(36)-thiazolinyl-CO 2R 51
(37)-thiazolinyl-C (O)-R 27a
(38) (CH 2) p-thiazolinyl-CO 2-R 51
(39)-(CH 2) pC=NOR 51And
(40)-(CH 2) p-phthalic imidine;
P is 0,1,2,3 or 4;
Each R 1With R 2Be independently selected from:
(1)H；
(2) halogen;
(3)-CF 3；
(4)-OR 10；
(5)-COR 10；
(6)-SR 10；
(7)-S (O) tR 15, wherein t is 0,1 or 2;
(8)-N(R 10) 2：
(9)-NO 2；
(10)-OC(O)R 10；
(11)-CO 2R 10；
(12)-OCO 2R 15；
(13)-CN；
(14)-NR 10COOR 15；
(15)-SR 15C(O)OR 15；
(16)-SR 15N (R 13) 2, its condition is at-SR 15N (R 13) 2In R 15Be not-CH 2, and each R wherein 13Be independently selected from: H and-C (O) OR 15
(17) benzotriazole-1-base oxygen base;
(18) tetrazolium-5-base sulfenyl;
(19) substituted tetrazolium-5-base sulfenyl;
(20) alkynyl;
(21) thiazolinyl; And
(22) alkyl
This alkyl or alkenyl optional by halogen ,-OR 10Or-CO 2R 10Replace;
R 3With R 4Identical or different, and each represents H and R independently 1With R 2Any substituting group;
R 5, R 6, R 7And R 7aEach is expression independently: H ,-CF 3,-COR 10, alkyl or aryl, this alkyl or aryl is chosen quilt-S (O) wantonly tR 15,-NR 10COOR 15,
-C (O) R 10Or-CO 2R 10Replace, or R 5With R 6Together expression=O or=S;
R 8Be selected from:
Figure A0380472001051
With
R 9Be selected from:
(1) unsubstituted heteroaryl;
(2) substituted heteroaryl;
(3) alkoxy aryl;
(4) substituted alkoxy aryl;
(5) Heterocyclylalkyl;
(6) substituted Heterocyclylalkyl;
(7) Heterocyclylalkyl alkyl;
(8) substituted Heterocyclylalkyl alkyl;
(9) unsubstituted heteroaralkyl;
(10) substituted heteroaralkyl;
(11) unsubstituted heteroaryl thiazolinyl;
(12) substituted heteroaryl thiazolinyl;
(13) unsubstituted heteroaryl alkynyl; And
(14) substituted heteroaryl alkynyl;
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CO 2R 14；
(3)-CH 2OR 14；
(4) halogen (for example Br, Cl or F);
(5) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(6) amino;
(7) trityl;
(8) Heterocyclylalkyl;
(9) cycloalkyl (for example cyclopropyl or cyclohexyl);
(10) aralkyl;
(11) heteroaryl;
(12) heteroaralkyl, and
(13)
Figure A0380472001061
R wherein 14Be independently selected from: H; Alkyl; Aryl, aralkyl, heteroaryl and heteroaralkyl;
R 9aBe selected from: alkyl and aralkyl;
R 9bBe selected from:
(1)-C(O)R 9a；
(2)-SO 2R 9a；
(3)-C(O)NHR 9a；
(4)-C (O) OR 9aAnd
(5)-C(O)N(R 9c) 2；
Each R 9cBe independently selected from: H, alkyl and aralkyl;
R 10Be selected from: H; Alkyl; Aryl and aralkyl;
R 11Be selected from:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) Heterocyclylalkyl;
(10) substituted Heterocyclylalkyl;
(11) unsubstituted thiazolinyl (for example-CH 2CH=CH 2);
(12)-N (alkyl) 2, wherein each alkyl be independent the selection (for example-N (CH 3) 2);
(13) unsubstituted aralkyl; And
(14) substituted aralkyl;
This substituted alkyl R wherein 11Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2) halogen (for example Br, Cl or F); And
(3)-CN; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2) halogen (for example Br, Cl or F); And
(3) alkyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11The aryl moiety of group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2) halogen (for example Br, Cl or F);
(3) alkyl;
(4)-CF 3；
(5)-CN; And
(6) alkoxyl group (for example-OCH 3);
R 11aBe selected from:
(1)H；
(2)OH；
(3) alkyl;
(4) substituted alkyl;
(5) aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) Heterocyclylalkyl;
(12) substituted Heterocyclylalkyl;
(13)-OR 9a；
(14) unsubstituted aralkyl;
(15) substituted aralkyl;
(16) unsubstituted thiazolinyl;
(17) unsubstituted aryl-acyl (for example-C (O) phenyl); And
(18) unsubstituted heteroaralkyl (for example-CH 2-pyridyl); This substituted alkyl R wherein 11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen (for example Br, Cl or F);
(5) cycloalkyl;
(6) Heterocyclylalkyl;
(7) aralkyl;
(8) heteroaralkyl; And
(9) assorted thiazolinyl; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen (for example Br, Cl or F);
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl; And
(11) assorted thiazolinyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11aThe aryl moiety of group has one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen (for example Br, Cl or F);
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl;
(11) assorted thiazolinyl;
(12) aryloxy (for example-O-phenyl); And
(13) alkoxyl group (for example-OCH 3);
R 12Be selected from: H, alkyl, piperidine ring V, cycloalkyl and-(wherein this piperidine ring V is as mentioned below, consults, for example at R for alkyl-(piperidine ring V) 21, R 22And R 46Definition in paragraph (8));
R 15Be selected from: alkyl and aryl;
R 21, R 22And R 46Be independently selected from:
(1)-H；
(2) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(3) unsubstituted aryl (for example phenyl);
(4) be substituted aryl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(5) unsubstituted cycloalkyl (for example cyclohexyl);
(6) be substituted cycloalkyl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(7) following formula heteroaryl
With
Figure A0380472001102
(8) following formula Heterocyclylalkyl:
(meaning is piperidine ring V), wherein R 44Be selected from:
(a)-H；
(b) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(c) alkyl carbonyl (CH for example 3C (O)-);
(d) carbalkoxy (for example-C (O) O-t-C 4H 9,-C (O) OC 2H 5And-C (O) OCH 3);
(e) haloalkyl (for example trifluoromethyl); And
(f)-C(O)NH(R 51)；
(9)-NH 2, its condition is R 21, R 22And R 46Have only one to can be-NH in the group 2, and its condition is to work as R 21, R 22And R 46In one of be-NH 2The time, then all the other groups are not-OH;
(10)-and OH, its condition is R 21, R 22And R 46Have only one to can be-OH in the group, and its condition is to work as R 21, R 22And R 46In one of be-during OH, then all the other groups are not-NH 2And
(11) by one or more (for example 1-3 or 1-2, and preferred 1) alkyl that substituting group replaces, described substituting group is selected from :-OH and-NH 2, its condition is only one-OH or one-NH on substituted carbon 2Group;
(12) alkoxyl group (for example-OCH 3); Or
(13) R 21With R 22Form cyclic rings together with their institute's bonded carbon, described ring is selected from:
(a) unsubstituted cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl);
(b) cycloalkyl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(c) unsubstituted cycloalkenyl group
(d) cycloalkenyl group that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(e) Heterocyclylalkyl, for example following formula piperidines basic ring:
Figure A0380472001121
R wherein 44Be selected from:
(1)-H；
(2) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(3) alkyl carbonyl (CH for example 3C (O)-);
(4) carbalkoxy (for example-C (O) O-t-C 4H 9,-C (O) OC 2H 5And-C (O) OCH 3);
(5) haloalkyl (for example trifluoromethyl); And
(6)-C(O)NH(R 51)；
(f) unsubstituted aryl (for example phenyl);
(g) aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl (for example methyl), halogen (for example Cl, Br and F) ,-CN ,-CF 3, OH and alkoxyl group (for example methoxyl group); And
(i) heteroaryl, described heteroaryl is selected from:
Figure A0380472001122
With
Figure A0380472001123
R 26Be selected from:
(1)-H；
(2) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(3) alkoxyl group (for example methoxyl group, oxyethyl group or propoxy-);
(4)-CH 2-CN；
(5)R 9；
(6)-CH 2CO 2H；
(7)-C (O) alkyl; And
(8) CH 2CO 2Alkyl;
R 27Be selected from:
(1)-H；
(2)-OH；
(3) alkyl (for example methyl, ethyl, propyl group or butyl); And
(4) alkoxyl group;
R 27aBe selected from:
(1) alkyl (for example methyl, ethyl, propyl group or butyl); With
(2) alkoxyl group;
R 30, R 31, R 32And R 33Be independently selected from:
(1)-H；
(2)-OH；
(3)＝O；
(4) alkyl;
(5) aryl (for example phenyl);
(6) aralkyl (for example benzyl);
(7)-OR 9a；
(8)-NH 2；
(9)-NHR 9a；
(10)-N (R 9a) 2, each R wherein 9aBe independent the selection;
(11)-N 3；
(12)-NHR 9bAnd
(13)-N(R 9a)R 9b；
R 50Be selected from:
(1) alkyl;
(2) unsubstituted heteroaryl;
(3) substituted heteroaryl; And
(4) amino;
Wherein be substituted R at this 50Substituting group on the group is independently selected from: alkyl (for example methyl, ethyl, propyl group and butyl); Halogen (for example Br, Cl and F); And-OH;
R 51Be selected from: H and alkyl (for example methyl, ethyl, propyl group, butyl and the tertiary butyl); And its condition is:
(1) in substituted Heterocyclylalkyl part, the ring carbon atom adjacent with ring hetero atom do not replaced by heteroatoms or halogen atom; And
(2) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not exceeded a heteroatoms and replaces; And
(3) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not replaced by heteroatoms and halogen atom; And
(4) the ring carbon in being substituted cycloalkyl moiety is not exceeded a heteroatoms replacement; And
(5) carbon atom in being substituted moieties is not exceeded a heteroatoms replacement; And
(6) the same carbon atom in being substituted moieties had not only replaced by heteroatoms but also by halogen atom; And
(7) when A and B are independently selected from substituting group (1) to (31) and (34) to (39), R then 8Be not H; And
(8) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (2.0), R then 11Be selected from substituting group (11) to (14); And
(9) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (3.0), R then 11Be selected from substituting group (11) to (14); And
(10) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (13) to (18), and R 12Definition, or (b) R as mentioned 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (c) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V); And
(11) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (5.0), R then 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(12) in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (preferred (32)), and R 30To R 33When being selected from substituting group (1) to (6), R then 8Be selected from:
(a) (2.0), wherein R 11Be selected from substituting group (11) to (14),
(b) (3.0), wherein R 11Be selected from substituting group (11) to (14),
(c) (4.0), wherein (i) R 11aBe selected from substituting group (13) to (18), and R 12Define about formula 1.0 as mentioned, or (ii) R 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (iii) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), and
(d) (5.0), wherein R 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); Reach (13) and in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2(meaning is substituting group (8)), and R 8During for (2.0), R then 8Be not
With
(14) in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3(meaning is substituting group (11)), and R 8During for (2.0), R then 8Be not
Figure A0380472001152
The present invention also provides pharmaceutical composition, and it comprises the The compounds of this invention (for example formula 1.0 compounds) and the pharmaceutically acceptable carrier of significant quantity.
It is a kind of in the patient of needs treatment that the present invention also provides, and suppresses the method for farnesyl protein transferase, and it comprises at least a (a kind of usually) The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity.
The present invention also is provided among the patient who needs treatment, the method for treatment (or inhibition) tumour (meaning is a cancer), and it comprises at least a (a kind of usually) The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity.
The present invention also is provided among the patient who needs treatment, the method of treatment (or inhibition) tumour (meaning is a cancer), it comprises at least a (a kind of usually) The compounds of this invention (for example formula 1.0 compounds) and at least a chemotherapeutic (also being called antineoplastic agent or carcinostatic agent in the art) to the co-administered significant quantity of this patient.
The present invention also is provided among the patient who needs treatment, the method of treatment (or inhibition) tumour (meaning is a cancer), it comprises at least a (a kind of usually) The compounds of this invention (for example formula 1.0 compounds) and at least a chemotherapeutic (also being called antineoplastic agent or carcinostatic agent in the art) and/or radiation to the co-administered significant quantity of this patient.
The present invention also is provided among the patient who needs treatment, the method of treatment (or inhibition) tumour (meaning is a cancer), it comprises at least a (a kind of usually) The compounds of this invention (for example formula 1.0 compounds) and at least a signal transduction inhibitor to the co-administered significant quantity of this patient.
In the method for the invention, The compounds of this invention (for example formula 1.0 compounds) can (be anticipated promptly continuously) and chemotherapeutic or signal transduction inhibitor administration simultaneously or one after the other.
Detailed Description Of The Invention
When describing in this article,, be each treatment cycle otherwise between a given period, use medicine or compound in (for example weekly or per three Mondays inferior) unless point out in addition.
When using in this article, following term has following meaning, except as otherwise noted:
ADHPLC is the HPLC post that derives from ChiralTechnologies;
AUC-represents " area under curve ";
BOC-represents tertbutyloxycarbonyl;
CBZ-represents-C (O) OCH 2C 6H 5(meaning is a carbobenzoxy-(Cbz));
CH 2Cl 2-expression methylene dichloride;
CIMS-represents chemical ionization mass spectrometry;
Cmpd-represents compound;
DBU-represents 1, and the 8-diazabicyclo is [5.4.0] 11-7-alkene also;
DEAD-represents diethyl azodiformate;
DEC-represents EDCl, and it represents 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride;
DMF-represents N, dinethylformamide;
DPPA-represents the diphenylphosphine acylazide;
Et-represents ethyl;
Et 3N-represents TEA, and it represents triethylamine;
EtOAc-represents vinyl acetic monomer;
EtOH-represents ethanol;
FAB-represents FABMS, and it represents quick atomic collision mass spectrum;
HOBT-represents the I-hydroxybenzotriazole hydrate;
HRMS-represents high resolution mass spec;
IPA-represents Virahol;
I-PrOH-represents Virahol;
Me-represents methyl;
MeOH-represents methyl alcohol;
MH +-be illustrated in the hydrogen that molion in the mass spectrum adds molecule;
MS-represents mass spectrum;
NMM-represents N-methylmorpholine;
ODHPLC is the HPLC post that derives from ChiralTechnologies;
PPh 3-expression triphenyl phosphine;
Ph-represents phenyl;
Pr-represents propyl group;
SEM-represents 2,2-(trimethyl silyl) ethoxyl methyl;
TBDMS-represents t-butyldimethylsilyl;
T-BUTYL-represents-C-(CH 3) 3
TFA-represents trifluoracetic acid;
THF-represents tetrahydrofuran (THF);
Tr-represents trityl;
Tf-represents SO 2CF 3
At least one-expression one or more-(for example 1-6), more preferably 1-4, wherein with 1,2 or 3 for most preferably;
Thiazolinyl-expression straight chain and side chain carbochain have at least one carbon-carbon double bond, and contain 2-12 carbon atom, are preferably 2 to 6 carbon atoms, and 3 to 6 carbon atoms most preferably;
Alkoxyl group-expression moieties, alkyl covalently bind on the adjoining structural unit through Sauerstoffatom, for example methoxyl group, oxyethyl group, propoxy-, butoxy etc. as hereinafter definition;
Alkyl-expression straight chain and side chain carbochain, and contain one to 20 carbon atom, be preferably one to six carbon atom, more preferably one to four carbon atom; One or two carbon atom more preferably again;
The alkyl that alkyl carbonyl-expression defines as mentioned covalently bind in carbonyl moiety (CO-), for example-COCH 3
The alkyl that carbalkoxy-expression defines as mentioned covalently bind in carbonyl moiety (CO-), for example-C (O)-OC through Sauerstoffatom 2H 5
Alkynyl-expression straight chain and side chain carbochain have at least one carbon carbon triple bond, and contain 2-12 carbon atom, are preferably 2 to 6 carbon atoms, and most preferably are 2 to 4 carbon atoms;
Amino-expression-NH 2Part;
Antineoplastic agent-expression is the chemotherapeutic of opposing cancer effectively;
Aryl-expression carbocyclic ring family group, in unsubstituted carbocyclic ring family group, contain 6 to 15 carbon atoms, and has at least one aromatic ring (for example aryl is a phenyl ring), wherein the adoptable substitutable carbon atom of all of carbocyclic ring family group is the possible tie point that is intended to as this aryl, this aryl is not for being substituted or being substituted, this substituted aryl has one or more (for example 1 to 3) substituting group, and described substituting group is independently selected from: halogen, alkyl, hydroxyl, alkoxyl group, phenoxy group, CF 3,-C (O) N (R 18) 2,-SO 2R 18,-SO 2N (R 18) 2, amino, alkylamino, dialkylamino ,-COOR 23And-NO 2(this substituting group preferably is independently selected from: alkyl (C for example 1-C 6Alkyl), halogen (for example Cl and Br) ,-CF 3And-OH), each R wherein 18Be independently selected from: H, alkyl, aryl, aralkyl, heteroaryl and cycloalkyl, and R wherein 23Be selected from: alkyl and aryl;
The alkyl that aralkyl-expression defines as mentioned, its aryl that is defined as mentioned replaces;
The mix assorted alkyl of alkyl-be expressed as follows literary composition definition of aryl, its aryl that is defined as mentioned replaces;
The aryl moiety that aryloxy-expression defines as mentioned covalently bind on the proximity structure unit through Sauerstoffatom, for example-and O-phenyl (meaning is a phenoxy group);
Compound-when mentioning, comprise medicament as antibody as antineoplastic agent;
Simultaneously-expression (1) is gone up (for example, under the identical time) simultaneously in the time, or (2) are during the process of co-therapy timetable, under different time;
Continuously-mean one to be connected on after another;
Cycloalkenyl group-expression unsaturated carbocyclic family ring, in unsubstituted ring, have 3 to 20 carbon atoms, be preferably 3 to 7 carbon atoms, this cyclenes basic ring comprises at least one (common one) two key, and this cyclenes basic ring is not for being substituted or being substituted, this substituted cyclenes basic ring has one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from: alkyl (for example methyl and ethyl), halogen ,-CF 3And-OH;
Cycloalkyl-expression saturated carbon ring family ring, in unsubstituted ring, have 3 to 20 carbon atoms, be preferably 3 to 7 carbon atoms, this cycloalkyl ring is not for being substituted or being substituted, this substituted cycloalkyl ring has one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from: alkyl (for example methyl and ethyl), halogen ,-CF 3And-OH; The cycloalkyl ring that replaces of 1-for example, for example
Figure A0380472001191
Or
Figure A0380472001192
Or Or
Figure A0380472001194
Wherein this alkyl is generally C 1-C 6Alkyl often is C 1-C 2Alkyl, and be preferably methyl; Therefore,, included but not limited to by the example of methyl substituted cycloalkyl ring in the 1-position:
Or
Figure A0380472001196
Or
Figure A0380472001197
Or
The alkyl that cycloalkylalkyl-expression defines as mentioned, the cycloalkyl substituted that it is defined as mentioned;
Different-in being used in " different antineoplastic agent " wording the time, meaning these medicaments is not same compound or structure; Preferably, in the time of in being used in " different antineoplastic agent " wording, " difference " means not is antineoplastic agent from identical type; For example a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex;
Significant quantity is gone up in significant quantity-expression treatment; For example the amount of compound (or medicine) or radiation can cause: (a) one or more is because of sx, mitigation or disappearance that cancer caused, (b) reduce the tumour size, (c) eliminate tumour, and/or (d) the prolonged sickness static stabilization of tumour (growth containment); For example, in the treatment of lung cancer (for example nonsmall-cell lung cancer), significant quantity is for relaxing or eliminate the amount of cough, short of breath and/or pain in the treatment; Also for example treatment is gone up the fpt inhibitor of significant quantity for causing the amount of farnesylation effect reduction; The reduction that the farnesylation work is used can be passed through the analysis of pharmacokinetics marker, such as PrelaminA and HDJ-2 (DNAJ-2), uses this area technology known to record;
Halogen (or halogen)-expression fluorine, chlorine, bromine or iodine;
The alkyl that haloalkyl-expression defines as mentioned, it is replaced by halogen;
Heteroatoms-expression O, N or S atom;
Assorted thiazolinyl-expression straight chain and side chain carbochain, has at least one carbon-carbon double bond, and contain two to 20 carbon atoms, be preferably two to six carbon atom, be selected from by 1 to 3 :-O-,-S-and-heteroatoms of N-inserts, its condition is that this heteroatoms is not adjacent to each other when surpassing a heteroatoms;
Assorted alkyl-expression straight chain and side chain carbochain contains one to 20 carbon atom, is preferably one to six carbon atom, is selected from by 1 to 3 :-O-,-S-and-the heteroatoms insertion of N-, its condition is that heteroatoms is not adjacent to each other as above a heteroatoms time;
Assorted alkynyl-expression straight chain and side chain carbochain has at least one carbon carbon triple bond, and contains two to 20 carbon atoms, be preferably two to six carbon atom, be selected from by 1 to 3 :-O-,-S-and-heteroatoms of N-inserts, its condition is that heteroatoms is not adjacent to each other when surpassing a heteroatoms;
Heteroaryl-expression is not substituted or substituted cyclic group, having at least one is selected from: the heteroatoms of O, S or N (its condition is that any O and S atom are not adjacent to each other), this heteroaryl comprises O and S atom, this heteroatoms inserts the carbocyclic ring structure, and non-localized πDian Zi with enough numbers, so that aromatic character to be provided, wherein unsubstituted heteroaryl preferably contains 2 to 14 carbon atoms, and wherein this substituted heteroaryl is by one or more (for example 1,2 or 3) identical or different R 3A(suc as formula 1.1 definition) group replaces, and the example of heteroaryl includes but not limited to: for example 2-or 3-furyl, 2-or 3-thienyl, 2-, 4-or 5-thiazolyl, 2-, 4-or 5-imidazolyl, 2-, 4-or 5-pyrimidyl, the 2-pyrazinyl, 3-or 4-pyridazinyl, 3-, 5-or 6-[1,2, the 4-triazinyl], 3-or 5-[1,2,4-thiadiazolyl group], 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-indyl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, triazolyl, 2-, 3-or 4-pyridyl or 2-, 3-or 4-pyridyl N-oxide compound, wherein pyridyl N-oxide compound can be represented as:
Or
The thiazolinyl that the heteroaryl thiazolinyl-expression defines as mentioned, it is replaced by the heteroaryl as hereinafter definition;
The alkyl that heteroaralkyl-expression defines as mentioned, its heteroaryl that is defined as mentioned replaces;
The alkyl that the Heterocyclylalkyl alkyl-expression defines as mentioned, it is replaced by the Heterocyclylalkyl as hereinafter definition;
Heterocyclylalkyl-expression saturated carbon ring family ring contains 3 to 15 carbon atoms, is preferably 4 to 6 carbon atoms, and this carbocyclic ring is inserted by 1 to 3 assorted group, and assorted group is selected from :-O-,-S-or-NR 24, R wherein 24Be selected from: H, alkyl, aryl reach-C (O) N (R 18) 2, R wherein 18Definition as mentioned, the example of Heterocyclylalkyl includes but not limited to: 2-or 3-tetrahydrofuran base, 2-or 3-tetrahydro-thienyl, 2-, 3-or 4-piperidyl, 2-or 3-pyrrolidyl, 1-, 2-, 3-or 4-piperazinyl, 2-or 4-dioxane base, morpholinyl reach
Figure A0380472001211
The alkyl that the Heterocyclylalkyl alkyl-expression defines as mentioned, it is replaced by aforesaid Heterocyclylalkyl;
" follow work "-, mean medicament or composition by while or administration one after the other about combination therapy of the present invention;
Patient-expression Mammals, for example human;
One after the other-expression (1) uses a kind of composition ((a) compound of the present invention, or (b) chemotherapeutic, signal transduction inhibitor and/or radiotherapy) of this method, then uses one or more other compositions; After using a kind of composition, the administration behind this first kind of composition immediately basically of following a kind of composition, or a kind of composition can be behind this first kind of composition down, administration behind duration of response; Duration of response is realized the specific time quantum of maximum benefit by the administration from first kind of composition.
Position in three ring ring systems is:
In the compound, "+" or "-" among the ring II represents " (+)-isomer " or " (-)-isomer " respectively hereinafter.
Known as this area institute, from the key that specific atoms is drawn, wherein do not have any part and retouched end in this key, being expression is combined in methyl on this atom through this bond.For example:
Representative
Figure A0380472001222
Representative
Figure A0380472001224
With
Representative
It will be appreciated by those skilled in the art that numeral " 1 " and " 2 " in formula, for example
Figure A0380472001231
With
Be to represent isomer 1 and 2 respectively.One of isomer is
And one of isomer is:
For example, for following isomer,
Figure A0380472001241
With
A kind of isomer is
And a kind of isomer is:
Figure A0380472001244
For The compounds of this invention, it is to wish to get from order to first kind of isomer of the separator column that separates non-enantiomer mixture (for example by first kind of isomer that HPLC obtained) or be the derivative of this first kind of isomer that isomer 1 means this compound.It is to wish to get from order to second kind of isomer of the separator column that separates non-enantiomer mixture (for example by second kind of isomer that HPLC obtained) or be the derivative of this second kind of isomer that isomer 2 means this compound.
In a specific embodiments of formula 1.0 compounds, when having one (being preferably B) among A and the B at least for substituting group (32) or (33) (being preferably (32)), R then 30To R 33In have at least one to be selected from substituting group (7) to (13).
In a specific embodiments of formula 1.0 compounds, when having one (being preferably B) among A and the B at least for substituting group (32) or (33) (being preferably (32)), R then 30To R 33In have at least one to be selected from substituting group (7), (9), (10), (12) and (13).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2, and R 8During for (2.0), R then 11Be selected from substituting group (3) to (10).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2, and R 8During for (2.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3, and R 8During for (2.0), R then 11Be selected from substituting group (3) to (10).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3, and R 8During for (2.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2, and R 8During for (3.0), R then 11Be selected from substituting group (1) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2, and R 8During for (3.0), R then 11Be selected from substituting group (3) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2, and R 8During for (3.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3, and R 8During for (3.0), R then 11Be selected from substituting group (1) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3, and R 8During for (3.0), R then 11Be selected from substituting group (3) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3, and R 8During for (3.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have one at least for NH 2, and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and and alkyl-(piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have one at least for NH 2, and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (13) to (18), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (c) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have one at least for N 3, and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have one at least for N 3, and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (13) to (18), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (c) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl (piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2, and R 8During for (5.0), R then 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3, and R 8During for (5.0), R then 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13).
In a specific embodiments of formula 1.0:
(1) in A and B, have at least one (being preferably B) to be substituting group (32), and R 30With R 31When being selected from substituting group (1) to (6), R then 8Be selected from:
(a) (2.0), wherein R 11Be selected from substituting group (11) to (14),
(b) (3.0), wherein R 11Be selected from substituting group (11) to (14),
(c) (4.0), wherein (i) R 11aBe selected from substituting group (13) to (18), and R 12Define in the formula 1.0 as mentioned, or (ii) R 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (iii) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), and
(d) (5.0), wherein R 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(2) in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (2.0), R then 8Be not
With
(3) in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (2.0), R then 8Be not
Figure A0380472001281
In a specific embodiments of formula 1.0 compounds, when having one (being preferably B) among A and the B at least when the substituting group (32), R then 30Or R 31In have at least one to be selected from substituting group (7), (9), (10), (12) and (13).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (2.0), R then 11Be selected from substituting group (3) to (10).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (2.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (2.0), R then 11Be selected from substituting group (3) to (10).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (2.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (3.0), R then 11Be selected from substituting group (1) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (3.0), R then 11Be selected from substituting group (3) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (3.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (3.0), R then 11Be selected from substituting group (1) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (3.0), R then 11Be selected from substituting group (3) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (3.0), R then 11Be selected from substituting group (11) to (14).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (13) to (18), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (c) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (4) and (7) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (13) to (18), and R 12Define in the formula 1.0 as mentioned, or (b) R 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (c) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-NH 2(R for example 30For-NH 2, and R 31For H or alkyl (for example-CH 3)), and R 8During for (5.0), R then 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13).
In a specific embodiments of formula 1.0 compounds, in A and B, have at least one (being preferably B) to be substituting group (32), and R 30Or R 31In have at least one to be-N 3(R for example 30For-N 3, and R 31For H or alkyl (for example-CH 3)), and R 8During for (5.0), R then 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13).
It will be appreciated by those skilled in the art that formula 1.0 compounds also represent with formula 1.1 compounds:
Figure A0380472001301
Or its pharmacy acceptable salt or solvate, wherein:
(A) expression N or N one of among a, b, c and the d +O -, and all the other a, b, c and d group are represented CR 1(meaning promptly has R 1The carbon of group), each R on each carbon wherein 1Group is identical or different; Or
(B) each a, b, c and d group are represented CR 1(meaning promptly has R 1The carbon of group), each R on each carbon wherein 1Group is identical or different;
(C) the optional key of dotted line (---) expression;
(D) when this optional key (to C11) when not existing, X represents N or CH, and when this key (to C11) of choosing wantonly when existing, X represents C;
(E) when having optional key (meaning promptly has two keys between C-5 and C-6) between carbon atom 5 (meaning is C-5) and the carbon atom 6 (meaning is C-6), then have only an A substituting group to be combined on the C-5, and have only a B substituting group to be combined on the C-6, and A or B are not H;
(F) when not having optional key (meaning promptly has a singly-bound between C-5 and C-6) between carbon atom 5 and 6, then:
(1) have two A substituting groups to be combined on the C-5, wherein each A substituting group is independent the selection; And
(2) have two B substituting groups to be combined on the C-6, wherein each B substituting group is independent the selection; And
Have at least in (3) two A substituting groups and have at least to be a H in one or two B substituting group; And
Have at least in (4) two A substituting groups and have at least not to be a H in one or two B substituting group; (meaning promptly when a singly-bound is arranged between C-5 and C-6, be H one of in four substituting groups (A, A, B and B), and one not being H);
(G) A and B are independently selected from:
(1)-H；
(2)-R 9；
(3)-R 9-C(O)-R 9；
(4)-R 9-CO 2-R 9a；
(5)-(CH 2) pR 26；
(6)-C (O) N (R 9) 2, each R wherein 9Identical or different;
(7)-C(O)NHR 9；
(8)-C(O)NH-CH 2-C(O)-NH 2；
(9)-C(O)NHR 26；
(10)-(CH 2) pC(R 9)-O-R 9a；
(11)-(CH 2) P-1CH (R 9) 2, its condition is that p is not 0, and each R wherein 9Identical or different;
(12)-(CH 2) pC(O)R 9；
(13)-(CH 2) pC(O)R 27a；
(14)-(CH 2) pC (O) N (R 9) 2, each R wherein 9Identical or different;
(15)-(CH 2) pC(O)NH(R 9)；
(16)-(CH 2) pC (O) N (R 26) 2, each R wherein 26Identical or different;
(17)-(CH 2) pN (R 9)-R 9a(for example-CH 2-N (CH 2-pyridine)-CH 2-imidazoles);
(18)-(CH 2) pN (R 26) 2, each R wherein 26Identical or different (for example-(CH 2) p-NH-CH 2-CH 3);
(19)-(CH 2) pNHC(O)R 50；
(20)-(CH 2) pNHC(O) 2R 50；
(21)-(CH 2) pN (C (O) R 27a) 2, each R wherein 27aIdentical or different;
(22)-(CH 2) pNR 51C(O)R 27；
(23)-(CH 2) pNR 51C (O) R 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(24)-(CH 2) pNR 51C(O)NR 27；
(25)-(CH 2) pNR 51C (O) NR 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(26-(CH 2) pNR 51C (O) N (R 27a) 2, each R wherein 27aIdentical or different;
(27)-(CH 2) pNHSO 2N (R 51) 2, each R wherein 51Identical or different;
(28)-(CH 2) pNHCO 2R 50；
(29)-(CH 2) pNC(O)NHR 51；
(30)-(CH 2) pCO 2R 51；
(31)-NHR 9；
(32)
Figure A0380472001331
R wherein 30With R 31Identical or different, and each p is independent the selection; Its condition is to each
Group is worked as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl (for example phenyl) and aralkyl (for example benzyl);
(33)
R wherein 30, R 31, R 32And R 33Identical or different; Its condition is to work as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl (for example phenyl) and aralkyl (for example benzyl); And its condition is to work as R 32Or R 33In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 32Or R 33Be selected from: H, alkyl, aryl (for example phenyl) and aralkyl (for example benzyl);
(34)-thiazolinyl-CO 2R 9a
(35)-thiazolinyl-C (O) R 9a
(36)-thiazolinyl-CO 2R 51
(37)-thiazolinyl-C (O)-R 27a
(38) (CH 2) p-thiazolinyl-CO 2-R 51
(39)-(CH 2) pC=NOR 51And
(40)-(CH 2) p-phthalic imidine;
(H) p is 0,1,2,3 or 4;
(I) R 1Be selected from:
(1)H；
(2) halogen;
(3)-CF 3；
(4)-OR 10；
(5)COR 10；
(6)-SR 10；
(7)-S(O) tR 15；
(8)-N(R 10) 2；
(9)-NO 2；
(10)-OC(O)R 10；
(11)CO 2R 10；
(12)-OCO 2R 15；
(13)-CN；
(14)-NR 10COOR 15；
(15)-SR 15C(O)OR 15；
(16)-SR 15N (R 13) 2, each R wherein 13Be independently selected from: H and-C (O) OR 15, and its condition is at-SR 15N (R 13) 2In R 15Be not-CH 2
(17) benzotriazole-1-base oxygen base;
(18) tetrazolium-5-base sulfenyl;
(19) substituted tetrazolium-5-base sulfenyl;
(20) alkynyl;
(21) thiazolinyl;
(22) alkyl;
(23) alkyl that is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10
(24) thiazolinyl that is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10
(J) each R 3ABe independently selected from:
(1) halogen;
(2)-CF 3；
(3)-OR 10；
(4)COR 10；
(5)-SR 10；
(6)-S(O) tR 15；
(7)-N(R 10) 2；
(8)-NO 2；
(9)-OC(O)R 10；
(10)CO 2R 10；
(11)-OCO 2R 15；
(12)-CN；
(13)-NR 10COOR 15；
(14)-SR 15C(O)OR 15；
(15)-SR 15N (R 13) 2, each R wherein 13Be independently selected from: H and-C (O) OR 15, and its condition is at-SR 15N (R 13) 2In R 15Be not-CH 2
(16) benzotriazole-1-base oxygen base;
(17) tetrazolium-5-base sulfenyl;
(18) substituted tetrazolium-5-base sulfenyl;
(19) alkynyl;
(20) thiazolinyl;
(21) alkyl;
(22) alkyl that is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10And
(23) thiazolinyl that is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10
(K) m is 0,1 or 2;
(L) t is 0,1 or 2;
(M) R 5, R 6, R 7And R 7aRespectively be independently selected from:
(1)H；
(2)-CF 3；
(3)-COR 10；
(4) alkyl;
(5) unsubstituted aryl;
(6) alkyl that is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is selected from :-S (O) tR 15,-NR 10COOR 15,-C (O) R 10And-CO 2R 10And
(7) aryl that is replaced by one or more (for example 1,2 or 3) substituting group, described substituting group is selected from :-S (O) tR 15,-NR 10COOR 15,-C (O) R 10And-CO 2R 10Or
(N) R 5With R 6Together expression=O or=S;
(O) R 8Be selected from:
Figure A0380472001361
With
(P) R 9Be selected from:
(1) unsubstituted heteroaryl;
(2) substituted heteroaryl;
(3) unsubstituted alkoxy aryl;
(4) substituted alkoxy aryl;
(5) Heterocyclylalkyl;
(6) substituted Heterocyclylalkyl;
(7) Heterocyclylalkyl alkyl;
(8) substituted Heterocyclylalkyl alkyl;
(9) be not substituted heteroaralkyl;
(10) substituted heteroaralkyl;
(11) unsubstituted heteroaryl thiazolinyl;
(12) substituted heteroaryl thiazolinyl;
(13) unsubstituted heteroaryl alkynyl reaches
(14) substituted heteroaryl alkynyl;
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CO 2R 14；
(3)-CH 2OR 14；
(4) halogen (for example Br, Cl or F);
(5) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(6) amino;
(7) trityl;
(8) Heterocyclylalkyl;
(9) cycloalkyl (for example cyclopropyl or cyclohexyl);
(10) aralkyl;
(11) heteroaryl;
(12) heteroaralkyl, and
(13)
Figure A0380472001371
R wherein 14Be independently selected from: H; Alkyl; Aryl, aralkyl, heteroaryl and heteroaralkyl;
(Q) R 9aBe selected from: alkyl and aralkyl;
(R) R 9bBe selected from:
(1)-C(O)R 9a；
(2)-SO 2R 9a；
(3)-C(O)NHR 9a；
(4)-C (O) OR 9aAnd
(5)-C(O)N(R 9c) 2；
(S) each R 9cBe independently selected from: H, alkyl and aralkyl;
(T) R 10Be selected from: H; Alkyl; Aryl and aralkyl;
(U) R 11Be selected from:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) Heterocyclylalkyl; With
(10) substituted Heterocyclylalkyl;
(11) unsubstituted thiazolinyl (for example-CH 2CH=CH 2);
(12)-N (alkyl) 2, wherein each alkyl be independent the selection (for example-N (CH 3) 2
(13) unsubstituted aralkyl; And
(14) substituted aralkyl;
This substituted alkyl R wherein 11Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2) halogen (for example Br, Cl or F); And
(3)-CN; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2) halogen (for example Br, Cl or F); And
(3) alkyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11The aryl moiety of group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2) halogen (for example Br, Cl or F);
(3) alkyl;
(4)-CF 3；
(5)-CN; And
(6) alkoxyl group (for example-OCH 3);
(V) R 11aBe selected from:
(1)H；
(2)OH；
(3) alkyl;
(4) substituted alkyl;
(5) unsubstituted aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) Heterocyclylalkyl;
(12) substituted Heterocyclylalkyl;
(13)-OR 9a；
(14) unsubstituted aralkyl;
(15) substituted aralkyl;
(16) unsubstituted thiazolinyl;
(17) unsubstituted aryl-acyl (for example-C (O) phenyl); And
(18) be not substituted heteroaralkyl (for example-CH 2-pyridyl); And this substituted alkyl R wherein 11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen (for example Br, Cl or F);
(5) cycloalkyl;
(6) Heterocyclylalkyl;
(7) aralkyl;
(8) heteroaralkyl; And
(9) assorted thiazolinyl; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen (for example Br, Cl or F);
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl, and
(11) assorted thiazolinyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11aThe aryl moiety of group has one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen (for example Br, Cl or F);
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl;
(11) assorted thiazolinyl;
(12) aryloxy (for example-O-phenyl); And
(13) alkoxyl group (for example-OCH 3);
(W) R 12Be selected from: H, alkyl, piperidine ring V, cycloalkyl and-(wherein this piperidine ring V is as mentioned below, consults for example R for alkyl-(piperidine ring V) 21, R 22And R 46Paragraph in the definition (8));
(X) R 15Be selected from: alkyl and aryl;
(Y) R 21, R 22And R 46Be independently selected from:
(1)H；
(2) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(3) unsubstituted aryl (for example phenyl);
(4) be substituted aryl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(5) unsubstituted cycloalkyl (for example cyclohexyl);
(6) be substituted cycloalkyl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen, CF 3Or OH;
(7) following formula heteroaryl
Figure A0380472001411
Or
(8) piperidine ring V:
R wherein 44Be selected from:
(a)H；
(b) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(c) alkyl carbonyl (CH for example 3C (O)-);
(d) carbalkoxy (for example-C (O) O-t-C 4H 9,-C (O) OC 2H 5And-C (O) OCH 3);
(e) haloalkyl (for example trifluoromethyl); And
(f)-C(O)NH(R 51)；
(9)-NH 2, its condition is R 21, R 22And R 46Have only one to can be-NH in the group 2, and its condition is to work as R 21, R 22And R 46In one of be-NH 2The time, then all the other groups are not-OH;
(10)-and OH, its condition is R 21, R 22And R 46Have only one to can be-OH in the group, and its condition is to work as R 21, R 22And R 46In one of be-during OH, then all the other groups are not-NH 2And
(11) by one or more (for example 1-3 or 1-2, and be preferably 1) alkyl that substituting group replaces, described substituting group is selected from :-OH and-NH 2, and its condition is to have only one-OH or one-NH on substituted carbon 2Group;
(12) alkoxyl group (for example-OCH 3); Or
(13) R 21With R 22Form cyclic rings together with their institute's bonded carbon, described ring is selected from:
(a) unsubstituted cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl);
(b) cycloalkyl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(c) unsubstituted cycloalkenyl group
(d) cycloalkenyl group that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(e) Heterocyclylalkyl, for example following formula piperidines basic ring:
R wherein 44Be selected from:
(1)-H；
(2) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(3) alkyl carbonyl (CH for example 3C (O)-);
(4) carbalkoxy (for example-C (O) O-t-C 4H 9,-C (O) OC 2H 5And-C (O) OCH 3);
(5) haloalkyl (for example trifluoromethyl); And
(6)-C(O)NH(R 51)；
(f) unsubstituted aryl (for example phenyl);
(g) aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl (for example methyl), halogen (for example Cl, Br and F) ,-CN ,-CF 3, OH and alkoxyl group (for example methoxyl group); And
(i) heteroaryl, described heteroaryl is selected from:
With
(Z) R 26Be selected from:
(1)H；
(2) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(3) alkoxyl group (for example methoxyl group, oxyethyl group, propoxy-);
(4)-CH 2-CN；
(5)R 9；
(6)-CH 2CO 2H；
(7)-C (O) alkyl, and
(8) CH 2CO 2Alkyl;
(AA) R 27Be selected from:
(1)H；
(2)-OH；
(3) alkyl (for example methyl, ethyl, propyl group or butyl), and
(4) alkoxyl group;
(AB) R 27aBe selected from:
(1) alkyl (for example methyl, ethyl, propyl group or butyl); With
(2) alkoxyl group;
(AC) R 30, R 31, R 32And R 33Be independently selected from:
(1)-H；
(2)-OH；
(3)＝O；
(4) alkyl;
(5) aryl (for example phenyl);
(6) aralkyl (for example benzyl);
(7)-OR 9a；
(8)-NH 2；
(9)-NHR 9a；
(10)-N (R 9a) 2, each R wherein 9aBe independent the selection;
(11)-N 3；
(12)-NHR 9bAnd
(13)-N(R 9a)R 9b；
(AD) R 50Be selected from:
(1) alkyl;
(2) unsubstituted heteroaryl;
(3) substituted heteroaryl; And
(4) amino;
Wherein be independently selected from one or more (for example 1,2 or 3) substituting group at this substituting group that is substituted on the heteroaryl, described substituting group is selected from: alkyl (for example methyl, ethyl, propyl group or butyl); Halogen (for example Br, Cl or F); And-OH;
(AE) R 51Be selected from: H and alkyl (for example methyl, ethyl, propyl group, butyl and the tertiary butyl); And
(AF) its condition is
(1) in substituted Heterocyclylalkyl part, the ring carbon atom adjacent with ring hetero atom do not replaced by heteroatoms or halogen atom; And
(2) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not exceeded a heteroatoms and replaces; And
(3) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not replaced by heteroatoms and halogen atom; And
(4) the ring carbon in being substituted cycloalkyl moiety is not exceeded a heteroatoms replacement; And
(5) carbon atom in being substituted moieties is not exceeded a heteroatoms replacement; And
(6) the same carbon atom in being substituted moieties had not only replaced by heteroatoms but also by halogen atom; And
(7) when A and B are independently selected from substituting group (1) to (31) and (34) to (39), R then 8Be not H; And
(8) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (2.0), R then 11Be selected from substituting group (11) to (14); And
(9) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (3.0), R then 11Be selected from substituting group (11) to (14); And
(10) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (13) to (18), and R 12Definition, or (b) R as mentioned 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (c) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V); And
(11) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (5.0), R then 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(12) in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33When being selected from substituting group (1) to (6), R then 8Be selected from:
(a) (2.0), wherein R 11Be selected from substituting group (11) to (14),
(b) (3.0), wherein R 11Be selected from substituting group (11) to (14),
(c) (4.0), wherein (i) R 11aBe selected from substituting group (13) to (18), and R 12Define in the formula 1.0 as mentioned, or (ii) R 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (iii) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), and
(d) (5.0), wherein R 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); Reach (13) and in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2(meaning is substituting group (8)), and R 8During for (2.0), R then 8Be not
Figure A0380472001461
With
(14) in A and B, have at least one (being preferably B) to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3(meaning is substituting group (11)), and R 8During for (2.0), R then 8Be not
Figure A0380472001462
When a singly-bound is arranged between C-5 and C-6, then there are two A substituting groups to be combined on the C-5, and have two B substituting groups to be combined on the C-6,
Figure A0380472001463
Representative
Figure A0380472001464
And each A and each B are independent the selections, reaching to have at least in two A substituting groups has at least to be a H in one or two B substituting group, and have at least in two A substituting groups and have at least one (not anticipate promptly when a singly-bound is not arranged between C-5 and C-6 in one or two B substituting group for H, be H one of in four substituting groups (A, A, B and B), and one is not H).
Substituted R 9Group can be substituted on any position of the group with substitutable carbon atom.For example, have the group that is combined in the loop section (for example Heterocyclylalkyl or heteroaryl ring) on the hydrocarbon part (for example alkyl, alkenyl or alkynyl), can on this loop section and/or this hydrocarbon part, be substituted.Therefore, for example substituted heteroaralkyl can be substituted on this heteroaryl moieties and/or this moieties.
Piperidine ring V comprises following ring:
With
Figure A0380472001472
The example of ring V includes but not limited to:
Figure A0380472001473
Figure A0380472001474
With
A specific embodiments of the present invention relates to formula 1.1 compounds, and wherein the two keys of C-5 to C-6 exist, and A is H, and B is following group:
Figure A0380472001476
Wherein this B group-(CH 2) pThe p of-part is 0, and the p with the lower section of this B group wherein
Be 1, and every other substituting group all suc as formula in 1.1 define.Preferably, R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl (for example substituted imidazolyl).Most preferably, R 9Be substituted heteroaryl, more preferably substituted imidazolyl, N-alkyl imidazole base more preferably again, and again more preferably
Figure A0380472001482
Preferably, R 30Be selected from :-OH ,-NH 2,-OR 9a(R wherein 9aBe C 1To C 3Alkyl), N 3And-NHR 9b, and R 31Be selected from: H and alkyl (for example methyl).Most preferably, (1) R 30For-OH, and R 31Be H; (2) R 30For-NH 2, and R 31Be H; (3) R 30For-OR 9a(R wherein 9aBe C 1To C 3And R alkyl), 31Be H or alkyl (C for example 1-C 6, C 1-C 4, C 1-C 2, this alkyl is preferably methyl), and be preferably H; (4) R 50Be N 3, and R 31Be H or alkyl (C for example 1-C 6, C 1-C 4, C 1-C 2, this alkyl is preferably methyl), and be preferably H; Or (5) R 30For-NHR 9b(R wherein 9bSuc as formula in 1.1 define), and R 31Be H or alkyl (C for example 1-C 6, C 1-C 4, C 1-C 2, this alkyl is preferably methyl), and be preferably H.More preferably, R 30For-NH 2Or-NHR 9b, and R 31Be H.Again more preferably, R 30For-NH 2, and R 31Be H.Preferred X is N.Preferred a is N.Preferred b is CR 1, R wherein 1Be H.Preferred c is CR 1, R wherein 1Be H or halogen (for example Br or Cl), and most preferably be H.Preferred d is CR 1, R wherein 1Be H.Preferred R 5, R 6, R 7And R 7aBe H.Preferred m is 1, and R 3ABe halogen (for example Br or Cl), and most preferably be Cl.When m is 1, R 3APreferably in the C-8 position, meaning is preferred R 3ABe the 8-halogen, and most preferably be 8-Cl.R 8Be preferably 2.0,3.0,4.0 or 5.0.Work as R 8Be 2.0 o'clock, R 11Be preferably alkyl (C for example 1To C 4), most preferably be the tertiary butyl or sec.-propyl, and sec.-propyl more preferably.Preferred R 8Be 2.0.The compound of this specific embodiments preferably has the stereochemistry shown in formula 1.5A, 1.6A or the 1.7A.
A specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Wherein:
(1) a, b, c, d, R 3A, R 5, R 6, R 7, R 7a, R 8And X all such as about in the formula 1.1 definition;
(2) B is following group:
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Figure A0380472001493
Be 1 to 3, be preferably 1 to 2, most preferably be 1;
(c) for the lower section, when p is 1
R then 30Be selected from :-OH or-NH 2(be preferably-OH), and R 31Be alkyl, most preferably be C 1-C 6Alkyl, more preferably C 1-C 4Alkyl, C more preferably again 1-C 2Alkyl, and methyl more preferably again;
(d) for the lower section, when p is 2 or 3
Figure A0380472001502
Then: (1) is to one-CR 30R 31-part, R 30Be selected from :-OH or-NH 2, and R 31Be alkyl, most preferably be C 1-C 6Alkyl, more preferably C 1-C 4Alkyl, C more preferably again 1-C 2Alkyl, and methyl more preferably again; With (2) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; And
(e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30For-OH or-NH 2The time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part.
Another specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Wherein:
(1) R 8With X all such as about in the formula 1.1 definition;
(2) B is following group:
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Figure A0380472001513
Be 1 to 3, be preferably 1 to 2, most preferably be 1;
(c) for the lower section, when p is 1
Figure A0380472001521
R then 30Be selected from :-OH or-NH 2, and R 31Be alkyl, most preferably be C 1-C 6Alkyl, more preferably C 1-C 4Alkyl, C more preferably again 1-C 2Alkyl, and methyl more preferably again;
(d) for the lower section, when p is 2 or 3
Figure A0380472001522
Then: (1) is to one-CR 30R 31-part, R 30Be selected from :-OH or-NH 2, and R 31Be alkyl, most preferably be C 1-C 6Alkyl, more preferably C 1-C 4Alkyl, C more preferably again 1-C 2Alkyl, and methyl more preferably again; With (2) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; And
(e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30For-OH or-NH 2The time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(4) a is N;
(5) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen (for example Br, Cl or F), and all the other two R 1Substituting group is a hydrogen;
(6) m is 1, and R 3ABe halogen (for example Br or Cl), or m is 2, and each R 3AIdentical or different halogen (for example Br or Cl); And
(7) R 5, R 6, R 7And R 7aBe H.
Another specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Wherein:
(1) R 8Be such as about in the formula 1.0 definition;
(2) B is following group:
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Figure A0380472001533
Be 1 to 3, be preferably 1 to 2, most preferably be 1;
(c) for the lower section, when p is 1
Figure A0380472001541
R then 30Be selected from :-OH or-NH 2, and R 31Be alkyl, most preferably be C 1-C 6Alkyl, more preferably C 1-C 4Alkyl, C more preferably again 1-C 2Alkyl, and methyl more preferably again;
(d) for the lower section, when p is 2 or 3
Figure A0380472001542
Then: (1) is to one-CR 30R 31-part, R 30Be selected from :-OH or-NH 2, and R 31Be alkyl, most preferably be C 1-C 6Alkyl, more preferably C 1-C 4Alkyl, C more preferably again 1-C 2Alkyl, and methyl more preferably again; With (2) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; And
(e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30For-OH or-NH 2The time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(4) a is N;
(5) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen (for example Br, Cl or F), and all the other two R 1Substituting group is a hydrogen;
(6) m is 1, and R 3ABe halogen (for example Br or Cl), or m is 2, and each R 3AIdentical or different halogen (for example Br or Cl);
(7) X is N or CH; And
(8) R 5, R 6, R 7And R 7aBe H.
Another specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Figure A0380472001551
Wherein:
(1) a, b, c, d, R 3A, R 5, R 6, R 7, R 7a, R 8And X all such as about in the formula 1.1 definition;
(2) B is following group:
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Be 1 to 3, be preferably 1 to 2, most preferably be 1;
(c) for the lower section, when p is 1
Then
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and methyl more preferably, for example-OR 9aFor-OCH 3
(2)-N 3；
(3)-NHR 9b, R wherein 9bBe such as about in the formula 1.1 definition; And
(4)-N (R 9a) R 9b, R wherein 9aWith R 9bBe such as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl);
(d) for the lower section, when p is 2 or 3
Figure A0380472001562
Then:
(i) to one-CR 30R 31-part
(1) R 30For-OH, and R 31Be H; Or
(2) R 30For-NH 2, and R 31Be H; Or
(3) R 30Be selected from:
(a)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and methyl more preferably,
For example-OR 9aFor-OCH 3
(b)-N 3；
(c)-NHR 9b, R wherein 9bBe such as about in the formula 1.1 definition; And
(d)-N (R 9a) R 9b, R wherein 9aWith R 9bBe such as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 2Alkyl and methyl); And
(ii) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; Reach (e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part.
Another specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Wherein:
(1) R 8With X all such as about in the formula 1.0 definition;
(2) B is following group:
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Be 1 to 3, be preferably 1 to 2, most preferably be 1;
(c) for the lower section, when p is 1
Then
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and methyl more preferably, for example-OR 9aFor-OCH 3
(2)-N 3；
(3)-NHR 9b, R wherein 9bBe such as about in the formula 1.1 definition; And
(4)-N (R 9a) R 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl);
(d) for the lower section, when p is 2 or 3
Figure A0380472001591
Then:
(i) to one-CR 30R 31-part
(1) R 30For-OH, and R 31Be H; Or
(2) R 30For-NH 2, and R 31Be H; Or
(3) R 30Be selected from:
(a)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and methyl more preferably, for example-OR 9aFor-OCH 3
(b)-N 3；
(c)-NHR 9b, R wherein 9bBe such as about in the formula 1.1 definition; And
(d)-N (R 9a) R 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 2Alkyl and methyl); And
(ii) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; Reach (e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(4) a is N;
(5) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen (for example Br, Cl or F), and all the other two R 1Substituting group is a hydrogen;
(6) m is 1, and R 3ABe halogen (for example Br or Cl), or m is 2, and each R 3AIdentical or different halogen (for example Br or Cl); And
(7) R 5, R 6, R 7And R 7aBe H.
Another specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Figure A0380472001601
Wherein:
(1) R 8Such as about in the formula 1.0 definition;
(2) B is following group:
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Figure A0380472001611
Be 1 to 3, be preferably 1 to 2, most preferably be 1;
(c) for the lower section, when p is 1
Figure A0380472001612
Then
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and methyl more preferably, for example-OR 9aFor-OCH 3
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-N (R 9a) R 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl);
(d) for the lower section, when p is 2 or 3
Then:
(i) to one-CR 30R 31-part
(1) R 30For-OH, and R 31Be H; Or
(2) R 30For-NH 2, and R 31Be H; Or
(3) R 30Be selected from:
(a)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and methyl more preferably, for example-OR 9aFor-OCH 3
(b)-N 3；
(c)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(d)-N (R 9a) R 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 2Alkyl and methyl); And
(ii) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; And
(e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(4) a is N;
(5) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen (for example Br, Cl or F), and all the other two R 1Substituting group is a hydrogen;
(6) m is 1, and R 3ABe halogen (for example Br or Cl), or m is 2, and each R 3AIdentical or different halogen (for example Br or Cl);
(7) X is N or CH; And
(8) R 5, R 6, R 7And R 7aBe H.
Another specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Figure A0380472001631
Wherein:
(1) a, b, c, d, R 3A, R 5, R 6, R 7, R 7a, R 8And X all such as about in the formula 1.1 definition;
(2) B is following group:
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Figure A0380472001633
Be 1;
(c)
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-N (R 9a) R 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl); And
(d) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part.
Another specific embodiments of the present invention relates to the formula 1.4E compound with following formula:
Figure A0380472001641
Wherein:
(1) R 8With X all such as about in the formula 1.0 definition;
(2) B is following group:
Figure A0380472001651
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Figure A0380472001652
Be 1;
(c)
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition;
And
(4)-N (R 9a) R 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl); And
(e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(4) a is N;
(5) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen (for example Br, Cl or F), and all the other two R 1Substituting group is a hydrogen;
(6) m is 1, and R 3ABe halogen (for example Br or Cl), or m is 2, and each R 3AIdentical or different halogen (for example Br or Cl); And
(7) R 5, R 6, R 7And R 7aBe H.
Another specific embodiments of the present invention relates to formula 1.1 compounds with following formula:
Figure A0380472001661
Wherein:
(1) R 8Such as about in the formula 1.0 definition;
(2) B is following group:
Figure A0380472001662
(3) in this B group:
(a)-(CH 2) pThe p of-part is 0;
(b) with the p of lower section
Be 1;
(c)
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-N (R 9a) R 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And
R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl); And
(e) R 9Be unsubstituted heteroaryl (for example imidazolyl) or substituted heteroaryl, be preferably substituted heteroaryl, most preferably be the heteroaryl that is replaced by alkyl (for example methyl), more preferably substituted imidazolyl, the imidazolyl that is more preferably replaced by alkyl again more more preferably by methyl substituted imidazolyl, and is more preferably encircling on the nitrogen by methyl substituted imidazolyl more again, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(4) a is N;
(5) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen (for example Br, Cl or F), and all the other two R 1Substituting group is a hydrogen;
(6) m is 1, and R 3ABe halogen (for example Br or Cl), or m is 2, and each R 3AIdentical or different halogen (for example Br or Cl);
(7) X is N or CH; And
(8) R 5, R 6, R 7And R 7aBe H.
Another specific embodiments of the present invention relates to formula 1.2,1.3,1.4,1.4A, and 1.4B, 1.4C, 1.4D, 1.4E and 1.4F compound, wherein X is CH.
Another specific embodiments of the present invention relates to formula 1.2,1.3,1.4,1.4A, and 1.4B, 1.4C, 1.4D, 1.4E and 1.4F compound, wherein X is CH, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.2,1.3,1.4,1.4A, and 1.4B, 1.4C, 1.4D, 1.4E and 1.4F compound, wherein X is N.
Another specific embodiments of the present invention relates to formula 1.2,1.3,1.4,1.4A, and 1.4B, 1.4C, 1.4D, 1.4E and 1.4F compound, wherein X is N, and has (meaning promptly has two keys between C5 and C6) in the bond of selecting for use between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4 compounds, and wherein for the lower section, p is 1
Figure A0380472001681
And R 30For-NH 2
Another specific embodiments of the present invention relates to formula 1.4 compounds, and wherein for the lower section, p is 1
Figure A0380472001682
R 30For-NH 2, and X is N.
Another specific embodiments of the present invention relates to formula 1.4D compound, and wherein for the lower section, p is 1
R 30For-NH 2, R 31For-CH 3, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30For-OH, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30For-OH, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30For-OH, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30For-NH 2, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30For-NH 2, and R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30For-NH 2, and R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl).
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4A compound or formula 1.4B compound or formula 1.4C compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N, and has (meaning promptly has two keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30For-OH, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30For-OH, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30For-OH, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30For-NH 2, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30For-NH 2, and R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30For-NH 2, and R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl).
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4D compound, wherein R 30Be selected from: (1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N, and has (meaning promptly has two keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30For-OH, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30For-OH, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30For-OH, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30For-NH 2, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30For-NH 2, and R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30For-NH 2, and R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl).
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4E compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N, and has (meaning promptly has two keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30For-OH, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30For-OH, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30For-OH, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30For-NH 2, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30For-NH 2, and R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30For-NH 2, and R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl).
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4F compound, wherein R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl is preferably C 1-C 2Alkyl, and more preferably methyl (for example-OR 9aFor-OCH 3);
(2)-N 3；
(3)-NHR 9b, R wherein 9bSuch as about in the formula 1.1 definition; And
(4)-NR 9aR 9b, R wherein 9aWith R 9bSuch as about in the formula 1.1 definition; And R 31Be selected from: H and alkyl (C for example 1-C 6Alkyl, C 1-C 4Alkyl, C 1-C 2Alkyl and methyl), and X is N, and has (meaning promptly has two keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-OR 9a, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-OR 9a, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-OR 9a, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-N 3, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-N 3, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-N 3, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NHR 9b, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NHR 9b, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NHR 9b, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NR 9aR 9b, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NR 9aR 9a, R 31Be H, and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NR 9aR 9b, R 31Be H, X is N, and has (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-OR 9a, and R 31Be alkyl (for example methyl).
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-OR 9a, R 31Be alkyl (for example methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-OR 9a, R 31Be alkyl (for example methyl) that X is N, and have (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-N 3, and R 31Be alkyl (for example methyl).
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-N 3, R 31Be alkyl (for example methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-N 3, R 31Be alkyl (for example methyl) that X is N, and have (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4 E or 1.4F compound, wherein R 30For-NHR 9b, and R 31Be alkyl (for example methyl).
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NHR 9b, R 31Be alkyl (for example methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NHR 9b, R 31Be alkyl (for example methyl) that X is N, and have (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NR 9aR 9b, and R 31Be alkyl (for example methyl).
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NR 9aR 9b, R 31Be alkyl (for example methyl), and X is N.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or 1.4F compound, wherein R 30For-NR 9aR 9b, R 31Be alkyl (for example methyl) that X is N, and have (meaning promptly has one pair of keys between C5 and C6) at the optional key between C5 and C6.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E and 1.4F compound, wherein to R 30Substituting group-NHR 9b, 9b is preferably-C (O) R 9a, and more preferably-C (O) R 9a, R wherein 9aBe alkyl.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E and 1.4F compound, wherein to R 30Substituting group-NHR 9b, 9b is preferably-C (O) R 9a, and more preferably-C (O) R 9a, R wherein 9aBe alkyl; And R 31Be H.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 8Be formula 2.0, wherein R 11Such as about in the formula 1.0 definition.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 8Be formula 3.0, wherein R 11Such as about in the formula 1.0 definition.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 8Be 4.0, R wherein 11aWith R 12All such as about in the formula 1.0 definition.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 8Be 5.0, R wherein 21, R 22And R 46All such as about in the formula 1.0 definition.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 8Be formula 2.0, wherein R 11Be alkyl (for example sec.-propyl or the tertiary butyl).
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 8Be formula 2.0, wherein R 11Be alkyl (for example the sec.-propyl or the tertiary butyl, and be preferably sec.-propyl), R 30For-NH 2, and R 31Be H.
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E and 1.4F compound, wherein for R 30Substituting group-NHR 9b, 9b is preferably-C (O) R 9a, and more preferably-C (O) R 9a, R wherein 9aBe alkyl, and R 8Be formula 2.0, wherein R 11Be alkyl (for example sec.-propyl or the tertiary butyl).
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E and 1.4F compound, wherein for R 30Substituting group-NHR 9b, 9b is preferably-C (O) R 9a, and more preferably-C (O) R 9a, R wherein 9aBe alkyl, and R 31Be H, and R 8Be formula 2.0, wherein R 11Be alkyl (for example sec.-propyl or the tertiary butyl).
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, and wherein the substituting group a in ring I is N, and substituting group b, c and d in ring I are CR 1Group, and all these R 1Substituting group is H.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, and wherein the substituting group a in ring I is N, and substituting group b, c and d in ring I are CR 1Group, and this R on C-3 1Substituting group is a halogen, and this R on C-2 and C-4 1Substituting group is a hydrogen.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, and wherein m is 1, and R 3ABe halogen.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, and wherein m is 1, and R 5ABe Cl.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, and wherein m is 1, and R 3ABe the halogen on the C-8 position.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, and wherein m is 1, and R 3ABe the Cl on the C-8 position.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, and wherein m is 2, and each R 3AIdentical or different halogen, and this halogen is substituted on C-7 and C-8 position or C-8 and the C-10 position.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 9Be unsubstituted heteroaryl or substituted heteroaryl.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 9Be substituted heteroaryl.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 9Be substituted heteroaryl, wherein this heteroaryl is that coverlet replaces.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 9Be unsubstituted imidazolyl or substituted imidazolyl.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 9Be substituted imidazolyl.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 9Be substituted imidazolyl, wherein this imidazolyl is that coverlet replaces, and substituting group is alkyl (C for example 1To C 3Alkyl or C 1To C 2Alkyl), and this substituting group be preferably methyl.
Another specific embodiments of the present invention relates to any specific embodiments that relates to formula 1.4D, 1.4E and 1.4F, wherein R 9For
In another specific embodiments, R 8Be 2.0 in formula 1.2, R wherein 11Such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 3.0 in formula 1.2, R wherein 11Such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 4.0 in formula 1.2, R wherein 11aWith R 12All as definition about formula 1.0.
In another specific embodiments, R 8Be 5.0 in formula 1.2, R wherein 21, R 22And R 46All as definition about formula 1.0.
In another specific embodiments, R 8Be 2.0 in formula 1.3, R wherein 11Such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 3.0 in formula 1.3, R wherein 11Such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 4.0 in formula 1.3, R wherein 11aWith R 12All such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 5.0 in formula 1.3, R wherein 21, R 22With R 46All such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 2.0 in formula 1.4, R wherein 11Such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 3.0 in formula 1.4, R wherein 11Such as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 4.0 in formula 1.4, R wherein 11aWith R 12All as about in the formula 1.0 definition.
In another specific embodiments, R 8Be 5.0 in formula 1.4, R wherein 21, R 22And R 46All such as about in the formula 1.0 definition.
Preferably, in formula 1.3 and 1.4, all R 1Substituting group is H, or the R of C-3 1Be halogen, and at the R of C-2 and C-4 1Be hydrogen, most preferably be all R 1Substituting group is hydrogen.
Preferably, in formula 1.3 and 1.4, when m is 1, R then 3ABe preferably the Cl on the C-8 position.
In formula 1.3 and 1.4, when m was 2, then substituting group was 7,8-two halogens or 8,10-two halogens.
Preferably, in formula 1.3 and 1.4, the optional two keys between C5 and C6 exist, and meaning promptly preferably has a two key between C5 and C6.
Preferably, in formula 1.2 and 1.3, X is N.
Preferably, in formula 1.4, X is N.
Another specific embodiments of the present invention relates to formula 1.4 compounds with following formula:
Figure A0380472001791
Wherein all substituting groups all such as about in the formula 1.4 definition.R 8Be preferably 2.0, most preferably be 2.0, wherein R 11Be alkyl, more preferably 2.0, R wherein 11Be the tertiary butyl or sec.-propyl, and again more preferably 2.0, wherein R 11Be sec.-propyl.
Another specific embodiments of the present invention relates to formula 1.5 compounds with following formula:
Wherein all substituting groups all such as about in the formula 1.4 definition.R 8Be preferably 2.0, most preferably be 2.0, wherein R 11Be alkyl, more preferably 2.0, R wherein 11Be the tertiary butyl or sec.-propyl, and again more preferably 2.0, wherein R 11Be sec.-propyl.
Therefore, a specific embodiments of the present invention relates to formula 1.5 compounds with following formula:
Wherein all substituting groups all such as about in the formula 1.4 definition.R 8Be preferably 2.0, most preferably be 2.0, wherein R 11Be alkyl, more preferably 2.0, R wherein 11Be the tertiary butyl or sec.-propyl, and again more preferably 2.0, wherein R 11Be sec.-propyl.
Another specific embodiments of the present invention relates to formula 1.5 compounds with following formula:
Figure A0380472001802
Wherein all substituting groups all such as about in the formula 1.4 definition.R 8Be preferably 2.0, most preferably be 2.0, wherein R 11Be alkyl, more preferably 2.0, R wherein 11Be the tertiary butyl or sec.-propyl, and again more preferably 2.0, wherein R 11Be sec.-propyl.
In formula 1.2,1.3, in 1.4,1.5,1.6 and 1.7, R 9Be preferably:
Figure A0380472001811
Another specific embodiments of the present invention relates to formula 1.4D, 1.4E or the 1.4F compound with following formula:
Figure A0380472001812
Wherein all substituting groups all such as about among formula 1.4D, 1.4E or the 1.4F definition.Formula 1.5A compound comprises wherein R 8Be 2.0 compound, and comprise wherein R 8Be 2.0, R wherein 11Be alkyl (C for example 1To C 4, such as the sec.-propyl or the tertiary butyl) compound.R 8Be preferably 2.0, R 11Be sec.-propyl, R 30For-NH 2, and R 31Be H.
Another specific embodiments of the present invention relates to the formula 1.5A compound with following formula:
Figure A0380472001821
Wherein all substituting groups all such as about among formula 1.4D, 1.4E or the 1.4F definition.Formula 1.5A compound comprises wherein R 8Be 2.0 compound, and comprise wherein R 8Be 2.0, R wherein 11Be alkyl (C for example 1To C 4, such as the sec.-propyl or the tertiary butyl) compound.R 8Be preferably 2.0, R 11Be sec.-propyl, R 30For-NH 2, and R 31Be H.
Therefore, a specific embodiments of the present invention relates to the formula 1.5A compound with following formula:
Figure A0380472001822
Wherein all substituting groups all such as about among formula 1.4D, 1.4E or the 1.4F definition.Formula 1.5A compound comprises wherein R 8Be 2.0 compound, and comprise wherein R 8Be 2.0, R wherein 11Be alkyl (C for example 1To C 4, such as the sec.-propyl or the tertiary butyl) compound.R 8Be preferably 2.0, R 11Be sec.-propyl, R 30For-NH 2, and R 31Be H.
Another specific embodiments of the present invention relates to the formula 1.5A compound with following formula:
Figure A0380472001831
Wherein all substituting groups all such as about among formula 1.4D, 1.4E or the 1.4F definition.Formula 1.5A compound comprises wherein R 8Be 2.0 compound, and comprise wherein R 8Be 2.0, R wherein 11Be alkyl (C for example 1To C 4, such as the sec.-propyl or the tertiary butyl) compound.R 8Be preferably 2.0, R 11Be sec.-propyl, R 30For-NH 2, and R 31Be H.
At formula 1.4D, 1.4E, 1.4F, 1.5A, among 1.6A and the 1.7A, R 9Be preferably:
Formula 1.0 compounds comprise the R isomer:
Figure A0380472001841
Or
Figure A0380472001842
Wherein:
X is N or CH;
A is that N or C (are N or CR in 1.1A 1); And
Optional key between C-5 and C-6 exists, and B is H, or the optional key between C-5 and C-6 is not exist, and each B is H.
Formula 1.0 compounds also comprise the S isomer:
Or
Figure A0380472001844
Wherein:
X is N or CH (being preferably N);
A is that (in 1.1B, a is N or CR for N or C 1); And
Optional key between C-5 and C-6 exists, and A is H, or the optional key between C-5 and C-6 is not exist, and each A is H (the optional key between C-5 and C-6 preferably exists).
In a specific embodiments of formula 1.0 compounds, R 1, R 2, R 3And R 4Be independently selected from: H and halogen, more preferably H, Br, F and Cl, and more preferably H and Cl again.Representative formula 1.0 compounds comprise the compound that two halogens (for example 3,8-two halogens) and single halogen (for example 8-halogen) replace, for example: (a) 3-bromo-8-chlorine, (b) 3,8-dichloro, (c) 3-bromine, (d) 3-chlorine, (e) 3-fluorine, (f) 8-chlorine or (g) 8-bromine.
In a specific embodiments of formula 1.1 compounds, each R 1Be independently selected from: H and halogen, most preferably be H, Br, F and Cl, and more preferably H and Cl.Each R 3Be independently selected from: H and halogen, most preferably be H, Br, F and Cl, and more preferably H and Cl.Representative formula 1.1 compounds comprise the compound that two halogens (for example 3,8-two halogens) and single halogen (for example 3-halogen or 8-halogen) replace, for example: (a) 3-bromo-8-chlorine, (b) 3,8-dichloro, (c) 3-bromine, (d) 3-chlorine, (e) 3-fluorine, (f) 8-chlorine or (g) 8-bromine.
In a specific embodiments of the present invention, the substituting group a in formula 1.0 compounds is preferably C or N, and wherein N is preferred, and the substituting group a in formula 1.1 compounds is CR 1Or N, wherein N is preferred.
In a specific embodiments of the present invention, the R in formula 1.0 compounds 8Be selected from:
With
In a specific embodiments of the present invention, the R in formula 1.0 compounds 8Be 2.0 or 4.0; And R 8Be preferably 2.0.
In a specific embodiments of the present invention, for formula 1.0 compounds, R 11aBe selected from: alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, heteroaryl, substituted heteroaryl, unsubstituted cycloalkyl and substituted cycloalkyl, wherein:
(1) this substituted aryl and substituted heteroaryl R 11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from: halogen (being preferably Cl), cyano group ,-CF 3And alkyl;
(2) this substituted cycloalkyl R 11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from: fluorine, cyano group ,-CF 3And alkyl; And
(3) this substituted alkyl R 11aGroup is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is selected from: fluorine, cyano group and CF 3
In a specific embodiments of the present invention, for formula 1.0 compounds, R 11aBe selected from: alkyl, unsubstituted aryl, substituted aryl, be not substituted cycloalkyl and substituted cycloalkyl, wherein:
(1) this substituted aryl is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from: halogen, (being preferably Cl) ,-CN and CF 3With
(2) this substituted cycloalkyl is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from: fluorine ,-CN and CF 3
In a specific embodiments of the present invention, for 1.0 compounds, R 11aBe selected from: methyl, the tertiary butyl, phenyl, cyano-phenyl, chloro-phenyl-, fluorophenyl and cyclohexyl.In another specific embodiments, R 11aBe selected from: the tertiary butyl, cyano-phenyl, chloro-phenyl-, fluorophenyl and cyclohexyl.In another specific embodiments, R 11aBe cyano-phenyl (for example right-cyano-phenyl).
In a specific embodiments of the present invention, for formula 1.0 compounds, R 11Be selected from alkyl, unsubstituted cycloalkyl and substituted cycloalkyl, wherein this substituted cycloalkyl is replaced by 1,2 or 3 substituting group, and described substituting group is independently selected from: fluorine and alkyl (being preferably the methyl or the tertiary butyl).R 11Examples of groups comprises: methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, cyclohexyl or substituted cyclohexyl.In a specific embodiments of the present invention, R 11Be selected from: methyl, sec.-propyl, the tertiary butyl, cyclohexyl and fluorine cyclohexyl (being preferably right-fluorine cyclohexyl).In a specific embodiments of the present invention, R 11Be selected from: methyl, sec.-propyl, the tertiary butyl and cyclohexyl.In a specific embodiments of the present invention, R 11Be the tertiary butyl or cyclohexyl.In a specific embodiments of the present invention, R 11For 2.0 being the tertiary butyl, and R 11For 3.0 is methyl.In a specific embodiments of the present invention, R 11Be sec.-propyl.
In a specific embodiments of the present invention, for formula 1.0 compounds, R 12Be selected from: H and methyl.In a specific embodiments of the present invention, R 12Be H.
In a specific embodiments of the present invention, for formula 1.0 compounds, R 5, R 6, R 7And R 7aBe H.
In a specific embodiments of the present invention, for formula 1.0 compounds, R 9Be selected from:
(1) unsubstituted heteroaryl;
(2) substituted heteroaryl;
(3) alkoxy aryl;
(4) substituted alkoxy aryl;
(5) Heterocyclylalkyl;
(6) substituted Heterocyclylalkyl;
(7) Heterocyclylalkyl alkyl;
(8) substituted Heterocyclylalkyl alkyl;
(9) heteroaralkyl;
(10) substituted heteroaralkyl;
(11) heteroaryl thiazolinyl, and
(12) substituted heteroaryl thiazolinyl;
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-OH；
(2)-CO 2R 14, R wherein 14Be selected from: H and alkyl (for example methyl and ethyl), be preferably alkyl, most preferably be methyl or ethyl;
(3) by one or more (alkyl that for example 1,2 or 3 is preferably 1)-OH base replaces, for example-(CH 2) qOH, wherein q is 1-4, wherein q=1 is preferred;
(4) halogen (for example Br, F, I or Cl);
(5) alkyl is generally C 1-C 6Alkyl is preferably C 1-C 4Alkyl (for example methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl or butyl are preferably the sec.-propyl or the tertiary butyl);
(6) amino;
(7) trityl;
(8) Heterocyclylalkyl;
(9) aralkyl (for example benzyl);
(10) heteroaryl (for example pyridyl), and
(11) heteroaralkyl;
In a specific embodiments of the present invention, for formula 1.0 compounds, R 9Be selected from:
(1) Heterocyclylalkyl;
(2) substituted Heterocyclylalkyl;
(3) Heterocyclylalkyl alkyl;
(4) substituted Heterocyclylalkyl alkyl;
(5) unsubstituted heteroaralkyl;
(6) substituted heteroaralkyl;
(7) unsubstituted heteroaryl thiazolinyl reaches
(8) substituted heteroaryl thiazolinyl;
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-OH；
(2)-CO 2R 14, R wherein 14Be selected from: H and alkyl (for example methyl or ethyl) are preferably alkyl, and most preferably are methyl and ethyl;
(3) by one or more (alkyl that for example 1,2 or 3 is preferably 1)-OH base replaces, for example-(CH 2) qOH, wherein q is 1-4, wherein q=1 is preferred;
(4) halogen (for example Br or Cl);
(5) alkyl is generally C 1-C 6Alkyl is preferably C 1-C 4Alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl most preferably are the tertiary butyl);
(6) amino;
(7) trityl;
(8) Heterocyclylalkyl;
(9) aralkyl;
(10) heteroaryl, and
(11) heteroaralkyl;
In a specific embodiments of the present invention, for formula 1.0, R 9Be selected from:
(1) Heterocyclylalkyl;
(2) substituted Heterocyclylalkyl;
(3) Heterocyclylalkyl alkyl;
(4) substituted Heterocyclylalkyl alkyl;
(5) unsubstituted heteroaralkyl;
(6) substituted heteroaralkyl;
(7) unsubstituted heteroaryl thiazolinyl, and
(8) substituted heteroaryl thiazolinyl;
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1) halogen (for example Br or Cl);
(2) alkyl is generally C 1-C 6Alkyl is preferably C 1-C 4Alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl most preferably are the tertiary butyl);
(3) alkyl that is replaced by one or more (meaning promptly 1,2 or 3, be preferably 1)-OH base (for example-(CH 2) qOH, wherein q is 1-4, wherein q=1 is preferred);
(4) amino;
(5) trityl;
(6) aralkyl, and
(7) heteroaralkyl.
In a specific embodiments of the present invention, R 9Be selected from:
(1) Heterocyclylalkyl alkyl;
(2) substituted Heterocyclylalkyl alkyl;
(3) unsubstituted heteroaralkyl, and
(4) substituted heteroaralkyl;
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1) halogen (for example Br or Cl);
(2) alkyl is generally C 1-C 6Alkyl is preferably C 1-C 4Alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl most preferably are the tertiary butyl);
(3) amino; And
(4) trityl.
In a specific embodiments of the present invention, for formula 1.0, R 9Be selected from:
(1) Heterocyclylalkyl alkyl;
(2) substituted Heterocyclylalkyl alkyl;
(3) unsubstituted heteroaralkyl, and
(4) substituted heteroaralkyl;
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1) halogen (for example Br or Cl); With
(2) alkyl is generally C 1-C 6Alkyl is preferably C 1-C 4Alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl most preferably are the tertiary butyl).
In a specific embodiments of the present invention, for formula 1.0, R 9Be selected from:
(1) piperidyl;
(2) piperazinyl;
(3)-(CH 2) p-piperidyl;
(4)-(CH 2) p-piperazinyl;
(5)-(CH 2) p-morpholinyl, and
(6)-(CH 2) p-imidazolyl;
Wherein p is 0 to 1, and each R wherein 9The loop section of group is optional to be replaced by one, two or three substituting group, and described substituting group is independently selected from:
(1) halogen (for example Br or Cl); With
(2) alkyl is generally C 1-C 6Alkyl is preferably C 1-C 4Alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl most preferably are the tertiary butyl).
In a specific embodiments of the present invention, for formula 1.0, R 9Be selected from:
(1)-piperazinyl;
(2)-(CH 2) p-piperidyl;
(3)-(CH 2) p-imidazolyl; And
(4)-(CH 2) p-morpholinyl;
Wherein p is 1 to 4, and each R 9The loop section of group is optional to be replaced by one, two or three substituting group, and substituting group is independently selected from: methyl, ethyl and sec.-propyl.
In a specific embodiments of the present invention, for formula 1.0, R 9Be selected from :-(CH 2)-imidazolyl, wherein this imidazoles basic ring is optional by 1,2 or 3, is preferably 1 substituting group and replaces, and described substituting group is independently selected from: methyl or ethyl.
In a specific embodiments of the present invention, for formula 1.0, R 9For-(CH 2)-(2-methyl)-imidazolyl.
In a specific embodiments of the present invention, for formula 1.0, R 21, R 22And R 46In have one at least for H or alkyl.In a specific embodiments of the present invention, R 21With R 22Be H, and R 46Be not H or alkyl.In a specific embodiments of the present invention, R 21With R 22Be H, and R 46Be selected from: heteroaryl and Heterocyclylalkyl.
In a specific embodiments of the present invention, for formula 1.0, for this R 21, R 22Or R 46, heteroaryl is independently selected from: 3-pyridyl, 4-pyridyl, 3-pyridyl-N-oxide compound and 4-pyridyl-N-oxide compound.In a specific embodiments of the present invention, for this R 21, R 22Or R 46, heteroaryl is independently selected from: 4-pyridyl and 4-pyridyl-N-oxide compound.In a specific embodiments of the present invention, for this R 21, R 22Or R 46, heteroaryl is 4-pyridyl-N-oxide compound.
In a specific embodiments of the present invention, for formula 1.0, for R 21, R 22Or R 46, Heterocyclylalkyl is selected from piperidine ring V:
R wherein 44For-C (O) NHR 51In a specific embodiments of the present invention, R 51For-C (O) NH 2In a specific embodiments of the present invention, piperidine ring V is:
And in a specific embodiments of the present invention, ring V is:
Therefore, in a specific embodiments of the present invention, for formula 1.0, R 21, R 22And R 46Be independently selected from:
(1)H；
(2) aryl (most preferably being phenyl);
(3) heteroaryl, and
(4) Heterocyclylalkyl (meaning is piperidine ring V),
R wherein 21, R 22Or R 46In have one at least for H, and in a specific embodiments of the present invention, R 21With R 22Be H, and R 46Be not H, and in a specific embodiments of the present invention, R 21With R 22Be H, and R 46Be selected from: heteroaryl and Heterocyclylalkyl, again in a specific embodiments of the present invention, R 21With R 22Be H, and R 46Be piperidine ring V; Wherein the definition of heteroaryl and piperidine ring V as mentioned above.
In a specific embodiments of the present invention, for formula 1.0, A and B are independently selected from:
(1)-H；
(2)-R 9；
(3)-R 9-C(O)-R 9；
(4)-R 9-CO 2-R 9a；
(5)-C(O)NHR 9；
(6)-C(O)NH-CH 2-C(O)-NH 2；
(7)-C(O)NHR 26；
(8)-(CH 2) p(R 9) 2, each R wherein 9Identical or different;
(9)-(CH 2) pC(O)R 9；
(10)-(CH 2) pC(O)R 27a；
(11)-(CH 2) pC (O) N (R 9) 2, each R wherein 9Identical or different;
(12)-(CH 2) pC(O)NH(R 9)；
(13)-(CH 2) pNHC(O)R 50；
(14)-(CH 2) pNHC(O) 2R 50；
(15)-(CH 2) pN (C (O) R 27a) 2, each R wherein 27aIdentical or different;
(16)-(CH 2) pNR 51C(O)R 27；
(17)-(CH 2) pNR 51C (O) R 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(18)-(CH 2) pNR 51C(O)NR 27；
(19)-(CH 2) pNR 51C (O) NR 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(20)-(CH 2) pNR 51C (O) N (R 27a) 2, each R wherein 27aIdentical or different;
(21)-(CH 2) pNHSO 2N (R 51) 2, each R wherein 51Identical or different;
(22)-(CH 2) pNHCO 2R 50；
(23)-(CH 2) pCO 2R 51；
(24)-NHR 9；
(25)
Figure A0380472001931
R wherein 30With R 31Identical or different, and
(26)
R wherein 30, R 31, R 32And R 33Identical or different.
In a specific embodiments of the present invention, for formula 1.0, A and B are independently selected from:
(1)-H；
(2)-R 9；
(3)-R 9-C(O)-R 9；
(4)-R 9-CO 2-R 9a；
(5)-C(O)NHR 9；
(6)-(CH 2) p(R 9) 2, each R wherein 9Identical or different;
(7)-(CH 2) pC(O)R 9；
(8)-(CH 2) pC (O) N (R 9) 2, each R wherein 9Identical or different;
(9)-(CH 2) pC(O)NH(R 9)；
(10)-(CH 2) pNR 51C(O)R 27；
(11)-(CH 2) pNR 51C (O) R 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(12)-(CH 2) pNR 51C(O)NR 27；
(13)-(CH 2) pNR 51C(O)NR 27，
R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(14)-NHR 9And
(15)
Figure A0380472001941
R wherein 30With R 31Identical or different.
The example of A and B includes but not limited to:
With
Wherein p is 0,1,2,3 or 4.
The example of A and B also includes but not limited to:
Figure A0380472001951
With
Figure A0380472001952
The example of A and B also includes but not limited to:
With
Figure A0380472001955
With
Figure A0380472001956
Therefore, the example of B includes but not limited to:
Figure A0380472001961
With
Figure A0380472001962
Figure A0380472001963
With
Figure A0380472001964
The preferred embodiment of B comprises:
With
Figure A0380472001966
Figure A0380472001971
With
Figure A0380472001972
The more preferably example of B comprises:
With
Figure A0380472001976
With
Figure A0380472001977
The most preferably example of B is:
Figure A0380472001981
R 8Examples of groups includes but not limited to:
With
Figure A0380472001993
R 8Example also include but not limited to:
Figure A0380472002002
With
R 8Example also include but not limited to:
Figure A0380472002011
With
R 8Example also include but not limited to:
Figure A0380472002013
Figure A0380472002014
With
In a specific embodiments of the present invention,, when the optional key between C-5 and C-6 exists (meaning has two keys between C-5 and C-6), be H one of among A or the B then, and another is R for formula 1.0 9, and R 9Be selected from:
(1) heteroaryl;
(2) substituted heteroaryl;
(3) aralkyl;
(4) substituted aralkyl;
(5) alkoxy aryl;
(6) substituted alkoxy aryl;
(7) Heterocyclylalkyl;
(8) substituted Heterocyclylalkyl;
(9) Heterocyclylalkyl alkyl;
(10) substituted Heterocyclylalkyl alkyl;
(11) unsubstituted heteroaralkyl;
(12) substituted heteroaralkyl;
(13) thiazolinyl;
(14) substituted thiazolinyl;
(15) unsubstituted heteroaryl thiazolinyl; And
(16) substituted heteroaryl thiazolinyl,
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-OH；
(2)-CO 2R 14；
(3)-CH 2OR 14；
(4) halogen;
(5) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(6) amino;
(7) trityl;
(8) Heterocyclylalkyl;
(9) aralkyl;
(10) heteroaryl, and
(11) heteroaralkyl,
R wherein 14Be independently selected from: H; With alkyl, be preferably methyl and ethyl.
In a specific embodiments of the present invention, for formula 1.0, when one pair of key was arranged between C-5 and C-6, A was H, and B is R 9In a specific embodiments of the present invention, for formula 1.0, when one pair of key was arranged between C-5 and C-6, A was H, and B is R 9, R wherein 9Be selected from:
(1) aralkyl;
(2) substituted aralkyl;
(3) alkoxy aryl;
(4) substituted alkoxy aryl;
(5) Heterocyclylalkyl;
(6) substituted Heterocyclylalkyl;
(7) Heterocyclylalkyl alkyl;
(8) substituted Heterocyclylalkyl alkyl;
(9) unsubstituted heteroaralkyl;
(10) substituted heteroaralkyl;
(11) thiazolinyl;
(12) substituted thiazolinyl;
(13) unsubstituted heteroaryl thiazolinyl; And
(14) substituted heteroaryl thiazolinyl,
This substituted R wherein 9Group is replaced by one or more (for example 1,2 or 3) substituting group, and described substituting group is independently selected from:
(1)-OH；
(2) halogen (being preferably Br);
(3) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(4) amino; And
(5) trityl.
In a specific embodiments of the present invention, for formula 1.0, when two keys were between C-5 and C-6, A was H, and B is R 9, R wherein 9Be selected from:
(1) Heterocyclylalkyl alkyl;
(2) substituted Heterocyclylalkyl alkyl;
(3) unsubstituted heteroaralkyl; And
(4) substituted heteroaralkyl;
Wherein for this substituted R 9Group, the identical or different alkyl of substituting group (C for example 1-C 4Alkyl).
In a specific embodiments of the present invention, for formula 1.0, when one pair of key was arranged between C-5 and C-6, A was H, and B is R 9, R wherein 9Be selected from:
(1) unsubstituted heteroaryl (C 1-C 3) alkyl; With
(2) substituted heteroaryl (C 1-C 3) alkyl;
Wherein be substituted R for this 9The substituting group of group is definition as mentioned all.
In a specific embodiments of the present invention, for formula 1.0, when one pair of key was arranged between C-5 and C-6, A was H, and B is R 9, R wherein 9Be selected from:
(1) unsubstituted heteroaryl (C 1-C 3) alkyl, wherein unsubstituted heteroaryl-CH 2-be preferred; With
(2) substituted heteroaryl (C 1-C 3) alkyl, wherein substituted heteroaryl-CH 2-be preferred;
Wherein for this substituted R 9The substituting group of group be selected from one or more (for example 1,2 or 3, wherein preferred) identical or different alkyl with one (for example-CH 3,-C 2H 5,-C 3H 4, wherein-CH 3For preferred).
In a specific embodiments of the present invention, for formula 1.0, when one pair of key was arranged between C-5 and C-6, A was H, and B is R 9, R wherein 9Be selected from:
(1)-CH 2-imidazolyl;
(2) substituted imidazolyl-CH 2-;
(3)-(CH 2) 2-imidazolyl;
(4) substituted imidazolyl-(CH 2) 2-;
(5)-(CH 2) 3-imidazolyl;
(6) substituted imidazolyl-(CH 2) 3-;
(7)-CH 2-piperazinyl, and
(8)-CH 2-morpholinyl;
Wherein this is substituted R 9The substituting group of group be selected from one or more (for example 1,2 or 3, wherein preferred) identical or different alkyl with one (for example-CH 3,-C 2H 5,-C 3H 4, wherein-CH 3For preferred).Substituted imidazolyl is preferably selected from:
With
Wherein substituted imidazolyl:
For most preferably.
In a specific embodiments of the present invention, for formula 1.0, when one pair of key was arranged between C-5 and C-6, A was H, and B is R 9, R wherein 9Be substituted imidazolyl-CH 2-, wherein
For preferably.
In a specific embodiments of the present invention, for formula 1.0, when B is H, and A is R 9, and when a two key is arranged between C-5 and C-6, for the R of A 9Group for above about B described those.
In a specific embodiments of the present invention, for formula 1.0, when the optional key between C-5 and C-6 does not exist (meaning has singly-bound between C-5 and C-6), each A and each B are independent the selections, and the definition of A and B and mentioned above identical when optional key exists, its condition is when a singly-bound is arranged between C-5 and C-6, then one of in two A substituting groups, or be H (meaning promptly when a singly-bound is arranged, being necessary for H one of in four substituting groups (A, A, B and B) between C-5 and C-6) one of in two B substituting groups.
In a specific embodiments of the present invention, to formula 1.0 and the opinion on public affairs compound, a two key is arranged between C-5 and C-6.
Having stereochemical formula 1.0 compounds of C-11R-and S-comprises:
Figure A0380472002081
Wherein:
X is N or C;
Q is Br or Cl; And
Y is alkyl, aralkyl or heteroaralkyl.
The present invention also relates to and is selected from following compound:
Figure A0380472002101
The present invention also relates to and is selected from following compound:
Figure A0380472002132
Figure A0380472002141
With
Representative formula 1.0 compounds include but not limited to be selected from following compound:
Figure A0380472002161
With
Preferred compound of the present invention is selected from:
Figure A0380472002211
Figure A0380472002221
With
Preferred compound of the present invention also is selected from:
Figure A0380472002243
Figure A0380472002251
With
Figure A0380472002263
More preferably compound of the present invention is selected from:
Figure A0380472002271
With
More preferably compound of the present invention also is selected from:
Figure A0380472002273
Figure A0380472002301
With
Figure A0380472002302
Most preferred compound of the present invention is selected from:
Figure A0380472002303
With
Figure A0380472002312
Most preferred compound of the present invention also comprises:
Following formula: compound:
Figure A0380472002321
Figure A0380472002331
Figure A0380472002341
With
Figure A0380472002342
Has FPTIC 50In the scope of＜0.5nM to 7.9nM, and soft agar IC 50In the scope of＜0.5nM to 18nM.
Following formula: compound:
With
Has FPTIC 50In the scope of 0.18nM to 1.2nM, and soft agar IC 50In the scope of＜0.5nM to 1nM.
Another specific embodiments of the present invention relates to and is selected from following compound:
Another specific embodiments of the present invention relates to and is selected from following compound:
Figure A0380472002361
Drawn the lines to the loop systems, represented that indicated key can be connected on any commutable ring carbon atom.
Some compound of the present invention can different isomerization body (for example enantiomer, diastereomer, atropisomer) form exist.This invention is intended to comprise all this kind isomer, be pure form and be and mix thing mutually, comprise racemic mixture.Also comprise the enol form.
Some tricyclic compound is acid in nature, for example has the compound of carboxyl or phenolic hydroxyl group.These compounds can form pharmacy acceptable salt.The example of this kind salt can comprise sodium, potassium, calcium, aluminium, gold and silver salt.What also be intended to be included is and the formed salt of pharmaceutically acceptable amine, this amine such as ammonia, alkyl amine, hydroxyalkyl amine, N-methyl glucoside amine etc.
Some alkaline tricyclic compound also forms pharmacy acceptable salt, for example acid salt.For example, the pyrido nitrogen-atoms can form salt with strong acid, and has for example amino compound of alkali subtituent, also can form salt with weaker acid.Supply the example of the suitable acid of salt formation, be hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, oxysuccinic acid, FUMARIC ACID TECH GRADE, succsinic acid, xitix, maleic acid, methylsulfonic acid, and known other mineral acids and the carboxylic-acid in this area.Preparing these salt, is via free alkali form being contacted with the required acid of capacity, producing salt in a usual manner.Free alkali form can via with this salt with suitable rare alkali aqueous solution, such as the dilute aqueous soln of NaOH, salt of wormwood, ammonia and sodium bicarbonate is handled and is regenerated.This free alkali form salt forms indivedual with it, slightly different on some physical properties, such as the solubleness in polar solvent, but for the purposes of this invention, acid is equivalent to its indivedual free alkali forms in other respects with alkali salt.
All this kind acid and alkali salt are intended to be pharmaceutically-acceptable salts within the scope of the present invention, and for the purposes of this invention, all acid and alkali salt are considered to be equivalent to the free form of respective compound.
The compounds of this invention (for example formula 1.0 compounds) is solvent chemical combination and the existence of solvent chemical combination form not, comprises hydrated form, for example semihydrate.Generally speaking, have the solvent chemical combination form of pharmaceutically acceptable solvent such as water, ethanol etc., for the purposes of this invention, be equivalent to not solvent chemical combination form.
The compounds of this invention: (i) suppress farnesyl protein transferase in vitro effectively, but can not suppress geranyl geranyl protein transferase I; (ii) will be by becoming the conversion Ras form of farnesyl acceptor, but not change blocking-up by the conversion Ras form institute inductive phenotype that is transformed into geranyl geranyl acceptor; (iii) block the interior processing of born of the same parents of Ras, this Ras is the farnesyl acceptor, but not is transformed into the Ras of geranyl geranyl acceptor; And (iv) block in the culture by transforming Ras institute inductive abnormal cell growth.
The compounds of this invention can suppress farnesyl protein transferase, with the farnesylation effect of oncogene protein matter Ras.Therefore, the present invention further provides a kind of Mammals, especially among the mankind, by using one or more (for example a kind of) The compounds of this invention of significant quantity (for example significant quantity is gone up in treatment), to suppress the method for farnesyl protein transferase (for example ras farnesyl protein transferase).The compounds of this invention to suppress farnesyl protein transferase, can be used for treating cancer hereinafter described to patient's administration.
The invention provides a kind of inhibition or treat abnormal cells and comprise that by the method for transformed cell growth its mode is to use one or more (for example a kind of) The compounds of this invention of significant quantity (for example significant quantity is gone up in treatment).The misgrowth of cell refers to and the irrelevant cell growth (for example forfeiture of contact inhibition) of normal regulating mechanism.This comprises following misgrowth: (1) expresses the tumour cell (tumour) of activatory Ras oncogene; (2) tumour cell, wherein Ras protein is owing to the sudden change of the oncogene in the another kind of gene is activated; And the optimum and malignant cell of other proliferative diseases of unusual Ras activation wherein takes place in (3).
The present invention also provides a kind of method that suppresses or treat tumour (meaning is a cancer) growth, and its mode is that the Mammals of this kind of needs treatment (for example human) is used one or more (for example a kind of) The compounds of this invention of significant quantity (for example significant quantity is gone up in treatment).Particular words, the invention provides a kind of method that suppresses or treat the tumor growth of expressing activatory Ras oncogene, its mode is to use the above-claimed cpd of significant quantity (for example significant quantity is gone up in treatment).
The present invention also provides the especially method of cancer (meaning is a tumour) of a kind of treatment proliferative disease, and it comprises one or more (for example a kind of) the described herein The compounds of this invention of the co-administered significant quantity of the Mammals of this kind of needs treatment (for example human) (for example significant quantity is gone up in treatment) and at least a carcinostatic agent (meaning is a chemotherapeutic) and/or the radiation of significant quantity.
The present invention also provides the especially method of cancer (meaning is a tumour) of a kind of treatment proliferative disease, and it comprises one or more (for example a kind of) The compounds of this invention of the co-administered significant quantity of the Mammals of this kind of needs treatment (for example human) (for example significant quantity is gone up in treatment) and at least a signal transduction inhibitor of significant quantity.
The example of the proliferative disease that can be suppressed or treat (tumour, meaning are cancer) includes but not limited to:
(A) lung cancer (for example adenocarcinoma of lung and nonsmall-cell lung cancer);
(B) pancreatic cancer (for example carcinoma of the pancreas, for example exocrine pancreas cancer);
(C) colorectal carcinoma (for example colorectal carcinoma, for example adenocarcinoma of colon and adenoma of colon);
(D) myeloid leukemia (for example acute myelogenous leukemia (AML), CML and CMML);
(E) Tiroidina follicular carcinoma;
(F) myelodysplastic syndrome (MDS);
(G) bladder cancer;
(H) epidermal carcinoma;
(I) melanoma;
(J) mammary cancer;
(K) prostate cancer;
(L) head and neck cancer (for example squamous cell carcinoma of head and neck);
(M) ovarian cancer;
(N) neurospongioma;
(O) cancer (for example fibrosarcoma and rhabdosarcoma) of mesenchyme origin;
(P) sarcoma;
(Q) four cancer knurls;
(R) spongioblastoma;
(S) kidney;
(T) hepatoma;
(U) non-Hodgkin lymphoma;
(V) multiple myeloma; And
(W) anaplasia thyroid carcinoma.
For example, specific embodiments of the present invention comprises the treatment method for cancer, wherein this cancer is selected from: carcinoma of the pancreas, lung cancer, myeloid leukemia, Tiroidina filter palpebral edema knurl, myelodysplastic syndrome, head and neck cancer, melanoma, mammary cancer, prostate cancer, ovarian cancer, bladder cancer, neurospongioma, epidermal carcinoma, colorectal carcinoma, non-Hodgkin lymphoma and multiple bone myelocytome, it comprises the The compounds of this invention of this patient being used significant quantity.
And for example, specific embodiments of the present invention comprises the treatment method for cancer, and wherein this cancer is selected from: lung cancer (for example nonsmall-cell lung cancer), head and neck cancer (for example squamous cell carcinoma of head and neck), bladder cancer, mammary cancer, prostate cancer and myeloid leukemia (for example CML and AML), non-Hodgkin lymphoma and multiple myeloma.
It is a kind of in the patient of needs treatment that the present invention also provides, the treatment method for cancer, it comprises one or more (for example a kind of) The compounds of this invention of significant quantity on the administering therapeutic, and at least two kinds of different antineoplastic agents of significant quantity are gone up in treatment, described antineoplastic agent is selected from: (1) taxanes, (2) iridium-platinum complex, (3) Urogastron (EGF) inhibitor, it is an antibody, (4) EGF inhibitor, it is a small molecules, (5) vascular endothelial growth factor (VEGF) inhibitor, it is an antibody, (6) VEGF kinase inhibitor, it is a small molecules, (7) estrogen receptor antagon or selective estrogen receptor modulators (SERM), (8) antitumor nucleoside derivates, (9) Ai Boxi ketone (Epothilone), (10) topology isomerase inhibitors, (11) vinca alkaloids, (12) antibody, it is that α V β 3 integrates plain inhibitor, (13) small molecules, and it is that α V β 3 integrates plain inhibitor, (14) folate antagonist, (15) ribonucleotide reductase inhibitor, (16) anthracycline antibiotics, (17) biological product, (18) Thalidomide (or relevant imide), and (19) Gleevec (imatinib mesylate).
It is a kind of in the patient of needs treatment that the present invention also provides, the treatment method for cancer, it comprises one or more (for example a kind of) The compounds of this invention and antineoplastic agent of significant quantity on the administering therapeutic, and described antineoplastic agent is selected from: (1) EGF inhibitor, and it is an antibody, (2) EGF inhibitor, it is a small molecules, (3) VEGF inhibitor, and it is an antibody, and (4) VEGF inhibitor, it is a small molecules.Radiotherapy also can be united use with the aforesaid combination therapy, anticipates promptly, and the method for above-mentioned use The compounds of this invention and antineoplastic agent combination also can comprise the radiation of significant quantity on the administering therapeutic.
The present invention also provides a kind of method for the treatment of leukemia (for example acute myeloid leukemia (AML) and chronic myeloid leukemia (CML)) in the patient of needs treatment, it comprises one or more (for example a kind of) The compounds of this invention of significant quantity on the administering therapeutic, and: (1) Gleevec (imatinib mesylate) and Interferon, rabbit, with treatment CML; (2) Gleevec (imatinib mesylate) with through the Interferon, rabbit of PEGization, to treat CML; (3) antitumor nucleoside derivates (for example Ara-C) is with treatment AML; Or (4) antitumor nucleoside derivates (for example Ara-C) and anthracycline antibiotics, with treatment AML.
It is a kind of in the patient of needs treatment that the present invention also provides, the method of treatment non-Hodgkin lymphoma, it comprises one or more (for example a kind of) The compounds of this invention of significant quantity on the administering therapeutic, and: (1) a kind of biological product (for example sharp figure diffusing (Rituxan)); (2) a kind of biological product (for example sharp figure looses) and antitumor nucleoside derivates (for example not reaching Rabin (Fludarabine)); Or (3) Genasense (BCL-2 is had antisense).
It is a kind of in the patient of needs treatment that the present invention also provides, the method of treatment multiple myeloma, it comprises one or more (for example a kind of) The compounds of this invention of significant quantity on the administering therapeutic, and: (1) proteoplast inhibitor (for example deriving from the PS-341 of Millenium); Or (2) Thalidomide (or relevant imide).
The present invention also provides a kind of treatment method for cancer, and it comprises the following material to significant quantity on patient's administering therapeutic of this kind of needs treatment:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor;
(13) α V β 3 integrates plain micromolecular inhibitor;
(14) folate antagonist;
(15) ribonucleotide reductase inhibitor;
(16) anthracycline antibiotics;
(17) biological product;
(18) Thalidomide (or relevant imide); And
(19) Gleevec (imatinib mesylate).
The present invention also provides a kind of treatment method for cancer, and it comprises the following material to significant quantity on patient's administering therapeutic of this kind of needs treatment: (a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; Or
(13) α V β 3 integrates plain micromolecular inhibitor;
(14) folate antagonist;
(15) ribonucleotide reductase inhibitor;
(16) anthracycline antibiotics;
(17) biological product; And
(18) Thalidomide (or relevant imide).
The present invention also provides a kind of treatment method for cancer, and it comprises the following material to significant quantity on patient's administering therapeutic of this kind of needs treatment:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; Or
(13) α V β 3 integrates plain micromolecular inhibitor;
(14) folate antagonist;
(15) ribonucleotide reductase inhibitor;
(16) anthracycline antibiotics; And
(17) biological product.
The present invention also provides a kind of treatment method for cancer, and it comprises the following material to significant quantity on patient's administering therapeutic of this kind of needs treatment:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; And
(13) α V β 3 integrates plain micromolecular inhibitor.
The present invention also provides a kind of method for the treatment of nonsmall-cell lung cancer, and it comprises the following material to significant quantity on patient's administering therapeutic of this kind of needs treatment:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; And
(13) α V β 3 integrates plain micromolecular inhibitor.
The present invention also provides a kind of method for the treatment of nonsmall-cell lung cancer, comprises the following material to significant quantity on patient's administering therapeutic of this kind of needs treatment:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) antitumor nucleoside derivates;
(4) topology isomerase inhibitors; And
(5) vinca alkaloids.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment nonsmall-cell lung cancer, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) carboplatin; And
(c) taxol.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment nonsmall-cell lung cancer, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) cis-platinum; And
(c) gemcitabine.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment nonsmall-cell lung cancer, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) carboplatin; And
(c) gemcitabine.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment nonsmall-cell lung cancer, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) carboplatin; And
(c) docetaxel.
It is a kind of in the patient of needs treatment that the present invention also provides, the treatment method for cancer, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) antineoplastic agent, described antineoplastic agent is selected from:
(1) EGF inhibitor, it is an antibody;
(2) EGF inhibitor, it is a small molecules;
(3) VEGF inhibitor, it is an antibody; And
(4) VEGF kinase inhibitor, it is a small molecules.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment head and neck squamous cell cancer, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) one or more antineoplastic agent, described antineoplastic agent is selected from:
(1) taxanes; With
(2) iridium-platinum complex.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment head and neck squamous cell cancer, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex; And
(3) antitumor nucleoside derivates (for example 5 FU 5 fluorouracil).
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment CML, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) Gleevec (imatinib mesylate); And
(c) Interferon, rabbit (for example Intron-A).
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment CML, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) Gleevec (imatinib mesylate); And
(c) Interferon, rabbit of PEGization (for example Peg-Intron and Pegasys).
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment AML, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) antitumor nucleoside derivates (for example cytosine arabinoside (meaning is Ara-C)).
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment AML, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) antitumor nucleoside derivates (for example cytosine arabinoside (meaning is Ara-C)); And
(c) anthracycline antibiotics.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment non-Hodgkin (Hodgkin) lymphomas, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) Rituximab (Rituximab) (sharp figure diffusing (Rituxan)).
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment non-Hodgkin lymphoma, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) Rituximab (Rituximab) (sharp figure diffusing (Rituxan)); And
(c) antitumor nucleoside derivates (for example not reaches Rabin (fludarabine) (meaning is F-ara-A).
It is a kind of in the patient of needs treatment that the present invention also provides, and treats the method for non-Hodgkin lymphoma, comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) Genasense (BCL-2 is had antisense).
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment multiple myeloma, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) proteoplast inhibitor (for example PS-341 (Millenium)).
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment multiple myeloma, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) Thalidomide or relevant imide.
It is a kind of in the patient of needs treatment that the present invention also provides, the method for treatment multiple myeloma, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula 1.0 compounds);
(b) Thalidomide.
The present invention also relates to the described cancer of treatment herein, particularly above-mentioned method for cancer, wherein except the administration of fpt inhibitor and antineoplastic agent, also before the treatment cycle, during or implement radiotherapy afterwards.
It is believed that the present invention also provides a kind of and suppresses or treat optimum and the method neoplasm disease, wherein Ras protein be since the sudden change of carinogenicity in other genes and activate with anomalous mode--meaning is that Ras gene itself is not activated into the oncogene form because of sudden change--wherein this inhibitions or treatment be by Mammals (for example mankind) to the treatment of this kind of needs, use one or more (for example a kind of) The compounds of this invention of significant quantity (for example treating upward significant quantity) and finish.For example, hyperplasia of prostate illness neurofibroma generates, or wherein Ras is the tumour that sudden change or overexpression owing to Tyrosine kinases oncogene (for example neu, src, abl, lck and fyn) are activated, and can be suppressed or treat by described tricyclic compound herein.
Can be used for the The compounds of this invention in the inventive method, can suppress or treat the misgrowth of cell.Do not wish to be bound by theory, it is believed that these compounds can be via suppressing the G-protein function, such as Rasp21, via blocking-up G-protein prenyl turn into and performance function so makes it can be used for proliferative disease such as tumor growth and treatment for cancer.Do not wish to be bound by theory, it is believed that these compounds can suppress the ras farnesyl protein transferase, and therefore show the anti-proliferative activity of opposing ras transformant.
Treat proliferative disease (cancer according to the present invention, meaning is a tumour) method, comprise a kind of passing through simultaneously or the The compounds of this invention of sequential application significant quantity and the chemotherapeutic and/or the radiation of significant quantity, with the excrescent method of treatment (inhibition) cell (comprising) through transformant.
In preferred specific embodiments, the inventive method is included among the patient who needs treatment, the method of treatment or inhibition tumor growth, its mode is simultaneously or the The compounds of this invention of sequential application (1) significant quantity, influences agent and/or radiotherapy with at least a antineoplastic agent, the microtubule of (2) significant quantity.For example, these methods specific embodiments relates to a kind of treatment and is selected from: the method for cancer of lung cancer, prostate cancer and myeloid leukemia.
Treat the method for proliferative disease according to the present invention, also comprise the optimum method with the neoplasm disease of treatment (inhibition), wherein Ras protein is because the sudden change of carinogenicity in other genes, and with anomalous mode be activated-Yi is that Ras gene itself is not activated because of being mutated into the oncogene form.This method comprises the patient to the treatment of this kind of needs, while or the The compounds of this invention of sequential application significant quantity and the antineoplastic agent and/or the radiotherapy of significant quantity.The example of the proliferative disease that this kind can be treated comprises: hyperplasia of prostate illness neurofibroma generates, or wherein Ras is the tumour that sudden change or overexpression owing to Tyrosine kinases oncogene (for example neu, src, abl, lck, lyn, fyn) are activated.
For radiotherapy, γ-radiate is into preferably.
Treat proliferative disease (cancer according to the present invention, meaning is a tumour) method, also be included in the excrescent method of (comprising through changing cell) of treatment (inhibition) cell among the patient who needs this kind treatment, its mode is while or the The compounds of this invention of sequential application significant quantity and at least a signal transduction inhibitor of significant quantity.
Type signal transduction inhibitor comprises but is not limited to:
(i) Bcr/abl kinase inhibitor, for example STI571 (Gleevec (imatinib mesylate));
(ii) Urogastron (EGF) acceptor inhibitor, kinase inhibitor (Iressa for example, OSI-774) with antibody (clothing nurse clone (Imclone): people such as C225[Goldstein (1995), ClinCancerRes.1:1311-1318] and the hard Nice (Abgenix) of Abel: ABX-EGF), reach (iii) HER-2/neu acceptor inhibitor, for example Herceptin _(trastuzumab).
The specific embodiments of methods of treatment of the present invention relates to the combination of using medicine (compound) and promptly the present invention relates to be used for the treatment of the combination treatment of cancer to treat cancer, to anticipate.It will be appreciated by those skilled in the art that medicine is usually individually with the pharmaceutical composition administration.Use comprise surpass a kind of medicine pharmaceutical composition within the scope of the invention.
The formulation administration that antineoplastic agent normally is easy to obtain with the clinicist, and normally (for example with recipe quantity administration under its normal circumstances, bibliography on doctor's table, the 56th edition, 2002 (by (Montvale of medical economics company, NJ07645-1742) publish, it discloses content and for reference in this paper) described in amount, or in the amount described in the preparation person's document that uses about medicament).
For example, fpt inhibitor can oral way (for example, with capsule) administration, and antineoplastic agent can the administration of intravenously mode, usually with IV solution.Use comprise surpass a kind of medicine pharmaceutical composition within the scope of the invention.
Fpt inhibitor and antineoplastic agent are to treat the effective dose administration, and to obtain acceptable result clinically, for example symptom or tumour alleviates or eliminate.Therefore, fpt inhibitor and antineoplastic agent can be in the treatment doubtful case simultaneously or successive administration.The administration of antineoplastic agent can be implemented according to treatment doubtful case known in the art.
Fpt inhibitor and antineoplastic agent are that it continued for one to seven week usually, and the typical case goes up repetition 6 to 12 times with treatment doubtful case administration.Generally speaking, the treatment doubtful case be continue one to around.Also can use the treatment doubtful case in one to three week.Also can use the treatment doubtful case in one to two week.In this treatment doubtful case or during the cycle, fpt inhibitor is administration every day, and antineoplastic agent is all administrations one or repeatedly.Generally speaking, but fpt inhibitor administration every day (meaning once a day promptly) is preferably every day twice, and one week of antineoplastic agent is administered once or per three weeks once.For example, taxanes (taxol (Taxol for example for example _) or docetaxel (Taxotere for example _)) can be administered once in a week or per three weeks once.
But, it will be appreciated by those skilled in the art that this treatment doubtful case can change according to patient's needs.Therefore, be used in the combination of the compound (medicine) in the inventive method, modification administration that can above-mentioned doubtful case.For example, during treatment cycle, fpt inhibitor can be discontinuously and discontinuous administration.Therefore, for example during treatment cycle, but a week is gone through in fpt inhibitor administration every day, interrupts a week then, uses this administration, repeats during treatment cycle.Perhaps, but fpt inhibitor administration every day went through for two weeks, and interrupted a week, used this administration, repeated during treatment cycle.Therefore, fpt inhibitor can administration every day during the cycle, goes through one or week how, and interrupts one or week how during the cycle, uses this administration pattern, repeats during treatment cycle.This discontinuous treatment can also fate be a benchmark, but not full week.For example, took medicine every day 1 to 6 day, do not take medicine 1 to 6 day, use this pattern, during the treatment doubtful case, repeat.Wherein do not take sky (or week) number of fpt inhibitor, may not equal wherein to take sky (or week) number of fpt inhibitor.Usually, if use the discontinuous doubtful case of taking medicine, sky or all numbers of then taking fpt inhibitor are to be equal to or greater than sky or all numbers of not taking the FpT inhibitor at least.
Antineoplastic agent can give via bolus injection agent or continous pouring.Antineoplastic agent can be during treatment cycle every day to weekly, or whenever biweekly, or per three weeks are once, or once give around every.If administration every day during treatment cycle, then taking medicine this every day to comprise treatment cycle week number discontinuously.For example, take medicine a week (or many days), do not take medicine a week (or many days) use this pattern, repeat during treatment cycle.
Fpt inhibitor can the oral way administration, preferably with solid dosage, capsule more preferably, and simultaneously total treatment go up effectively day clothes dosage can every day one to four part, or one to two part of separate dose administration, usually, it is to give once or twice in one day that effective dose is gone up in this treatment, is preferably one day twice.Fpt inhibitor can about 50 be administered once to about 400 milligrams amount every day, and can about 50 be administered once every day to about 300 milligrams amount.Fpt inhibitor generally is with about 50 to about 350 milligrams amount one day administered twice, be generally 50 milligrams to about 200 milligrams one day twice, be preferably about 75 milligrams to about 125 milligrams of one day administered twice, and most preferably be about 100 milligrams of one day administered twice.
If the patient responds or be very stable, then after treatment cycle is finished, can repeat this treatment cycle according to clinicist's judgement.When treatment cycle was finished, the patient can continue on fpt inhibitor under the same dose that treatment be used in the doubtful case, or if this dosage be lower than 200 milligrams one day twice, then can promote this dosage to 200 milligram one day twice.Sustainable this maintenance dose (in this kind situation, can reduce dosage, and the patient is sustainable under this reduction dosage) till the patient makes progress to some extent or no longer dosage had resistance.
With the antineoplastic agent that fpt inhibitor uses, be during treatment cycle with its normal prescribed dose administration (anticipate promptly, antineoplastic agent is the implementation criteria administration according to these drug administrations).For example: (a) to taxanes, about 30 to about 300 milligrams/square metre; (b) to cis-platinum, about 30 to about 100 milligrams/square metre; (c) to carboplatin, about 2 to about 8AUC; (d) to being the EGF inhibitor of antibody, about 2 to about 4 milligrams/square metre; (e) to being micromolecular EGF inhibitor, about 50 to about 500 milligrams/square metre; (f) to being the VEGF kinase inhibitor of antibody, about 1 to about 10 milligrams/square metre; (g) to being micromolecular VEGF inhibitor, about 50 to about 2400 milligrams/square metre; (h) to SERM, about 1 to about 20 milligrams; (i) join Xi Tabin (capecitabine) for antitumor nucleosides 5 FU 5 fluorouracil, gemcitabine and card, about 500 to about 1250 milligrams/square metre; (j) for antitumor nucleosides cytosine arabinoside (Ara-C), the 100-200 milligram/square metre/day, per 3 to 4 weeks went through 7 to 10 days, and be high dosage to recurrent leukemia and lymphoma, meaning promptly 1 to 3 restrains/square metre, went through one hour in per 12 hours, per three to around, take the 4-8 doses; (k) not reach Rabin (Fludarabine) (F-ara-A) for antitumor nucleosides, the 10-25 milligram/square metre/day, per 3 to 4 weeks; (1) for antitumor nucleosides De Xitabin (Decitabine), 30 to 75 milligrams/square metre, per 6 weeks went through three days, the highest 8 cycles; (m) for antitumor nucleosides chlorine Desoxyadenosine (CdA, 2-CdA), 0.05-0.1 milligram/kg/day, with continous pouring, per 3 to 4 weeks went through paramount 7 days; (n) to Ai Boxi ketone (Epothilone), about 1 to about 100 milligrams/square metre; (o) to the topology isomerase inhibitors, about 1 to about 350 milligrams/square metre; (p) to vinca alkaloids, about 1 to about 50 milligrams/square metre; (q) to folate antagonist Rheumatrex (MTX), the 20-60 milligram/square metre, via oral, IV or IM, per 3 to 4 weeks, middle dosage schedule of administration is 80-250 milligram/square metre IV, per 3 to 4 weeks are gone through 60 minutes, and the high dosage schedule of administration is 250-1000 milligram/square metre IV, and per 3 to 4 weeks give with formyl tetrahydrofolic acid; (r) to the general U.S.A of folate antagonist urge (Premetrexed) (Alimta), per 3 all 300-600 milligrams/square metre (the 1st day 10 minutes IV perfusion); (s) to ribonucleotide reductase inhibitor hydroxyurea (HU), 20-50 milligram/kg/day (causing blood counting to descend on demand); (t) to iridium-platinum complex RP-54780 (Eloxatin), per 3 to 4 all 50-100 milligrams/square metre (be preferred for solid tumor, such as nonsmall-cell lung cancer, colorectal carcinoma and ovarian cancer); (u) to the anthracycline antibiotics daunorubicin, 10-50 milligram/square metre/day IV, per 3 to 4 weeks went through 3-5 days; (v) anthracycline antibiotics is restrained Suo Hong rhzomorph (adriamycin) more, 50-100 milligram/square metre IV continous pouring, per 3 to 4 weeks are gone through 1-4 days, or 10-40 milligram/square metre IV weekly; (w) to anthracycline antibiotics according to reaching red rhzomorph, the 10-30 milligram/square metre, went through every day 1-3 days, per 3 to 4 weeks pour into slow IV, go through 10-20 minute; (x) to biological Interferon, rabbit (Intron-A, Roferon), 5 to 2,000 ten thousand IU, on every Wendesdays time; (y) biological PEGization Interferon, rabbit (PEG-Intron, Pegasys), 3 to 4 micrograms/kg/day chronic subcutaneous (up to the recurrence or loss of activity till); And (z) biological Li Tuximabai (Rituximab) (Rituxan) (antibody that is used for non-Hodgkin lymphoma), 200-400 milligram/square metre IV is gone through 4-8 week weekly, 6 totally months.
Gleevec (imatinib mesylate) can oral way uses, and its amount is for about 200 to about 800 mg/day.
Thalidomide (and relevant imide) can use by oral way, and its amount is for about 200 to about 800 mg/day, and can take medicine continuously or use, up to recurrence or toxic till.Consult, people such as Mitsiades for example, " apoptosis that is caused by the immunomodulatory thalidomide analogs in human multiple myeloma cells sends signal; Treatment hint property ", Blood, 99 (12): 4525-30, on June 15th, 2002, it discloses content and has supplied its reference in this paper.
For example, taxol (Taxol for example _) can about 50 to about 100 milligrams/square metre amount, be administered once weekly, wherein about 60 to about 80 milligrams/square metre is preferred.In another example, taxol (Taxol for example _) can about 150 to about 250 milligrams/square metre amount, per three weeks are administered once, wherein about 175 to about 225 milligrams/square metre is preferred.
In another example, docetaxel (Taxotere for example _) can about 10 to about 45 milligrams/square metre amount, be administered once weekly.In another example, docetaxel (Taxotere for example _) can about 50 to about 100 milligrams/square metre amount, per three weeks are administered once.
In another example, cis-platinum can about 20 to about 40 milligrams/square metre amount, be administered once weekly.In another example, cis-platinum can about 60 to about 100 milligrams/square metre amount, per three weeks are administered once.
In another example, it is about 2 to about 3 amount that carboplatin can provide AUC, is administered once weekly.In another example, it is about 5 to about 8 amount that carboplatin can provide AUC, and per three weeks are administered once.
Therefore, in an example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) taxol (Taxol for example _) be to be administered once weekly to about 100 milligrams/square metre amount with about 50, wherein about 60 to about 80 milligrams/square metre is preferred; And
(3) carboplatin is to be that about 2 to about 3 amount is administered once weekly so that AUC to be provided.
In another example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) taxol (Taxol for example _) be to be administered once weekly to about 100 milligrams/square metre amount with about 50, wherein about 60 to about 80 milligrams/square metre is preferred; And
(3) cis-platinum is to be administered once weekly to about 40 milligrams/square metre amount with about 20.
In another example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) docetaxel (Taxotere for example _) be to be administered once weekly to about 45 milligrams/square metre amount with about 10; And
(3) carboplatin is to be that about 2 to about 3 amount is administered once weekly so that AUC to be provided.
In another example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) docetaxel (Taxotere for example _) be to be administered once weekly to about 45 milligrams/square metre amount with about 10; And
(3) cis-platinum is to be administered once weekly to about 40 milligrams/square metre amount with about 20.
Therefore, in an example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) taxol (Taxol for example _) be to be administered once with about 150 to per three weeks of about 250 milligrams/square metre amount, wherein about 175 to about 225 milligrams/square metre is preferred, and wherein 175 milligrams/square metre for most preferably; And
(3) carboplatin is providing AUC to be administered once in about 5 to per three weeks of about 8 amount, and ACU is preferably 6.
In one of a treatment nonsmall-cell lung cancer preferred embodiment:
(1) fpt inhibitor is the amount one day administered twice with 100 milligrams;
(2) taxol (Taxol for example _) be to be administered once with per three weeks of 175 milligrams/square metre amount; And
(3) carboplatin is to be 6 be administered once in per three weeks of amount so that AUC to be provided.
In another example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) taxol (Taxol for example _) be to be administered once with about 150 to per three weeks of about 250 milligrams/square metre amount, wherein about 175 to about 225 milligrams/square metre is preferred; And
(3) cis-platinum is to be administered once with about 60 to per three weeks of about 100 milligrams/square metre amount.
In another example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) docetaxel (Taxotere for example _) be to be administered once with about 50 to per three weeks of about 100 milligrams/square metre amount; And
(3) carboplatin is to provide AUC to be administered once in about 5 to per three weeks of about 8 amount.
In another example, (for example treat nonsmall-cell lung cancer):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) docetaxel (Taxotere for example _) be to be administered once with about 50 to per three weeks of about 100 milligrams/square metre amount; And
(3) cis-platinum is to be administered once with about 60 to per three weeks of about 100 milligrams/square metre amount.
In a preferred embodiment that uses fpt inhibitor, docetaxel and carboplatin with the treatment nonsmall-cell lung cancer:
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice;
(2) docetaxel (Taxotere for example _) be to be administered once with per three weeks of about 75 milligrams/square metre amount; And
(3) carboplatin is to be about 6 be administered once in per three weeks of amount so that AUC to be provided.
In example above, docetaxel (Taxotere for example _) and cis-platinum, docetaxel (Taxotere for example _) and carboplatin, taxol (Taxol for example _) and carboplatin, or taxol (Taxol for example _) and cis-platinum, be preferable over administration on the same day.
In another example (for example CML):
(1) fpt inhibitor is with about 100 milligrams of extremely about 200 milligrams amount one day administered twice;
(2) Gleevec (imatinib mesylate) is with the oral way administration, and its amount is for about 400 to about 800 mg/day; And
(3) Interferon, rabbit (Intron-A) is to be administered three times weekly with about 5 amounts to about 2,000 ten thousand IU.
In another example (for example CML):
(1) fpt inhibitor is with about 100 milligrams of extremely about 200 milligrams amount one day administered twice;
(2) Gleevec (imatinib mesylate) is with the oral way administration, and its amount is for about 400 to about 800 mg/day; And
(3) Interferon, rabbit of PEGization (PEG-Intron or Pegasys) is with the about 3 amount administrations to about 6 micrograms/kg/day.
In another example (for example non-Hodgkin lymphoma):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice; And
(2) Genasense (BCL-2 is had antisense) is with continuous IV perfusion administration, and in about 2 to the dosage of about 5 milligrams/kg/day (for example 3 milligrams/kg/day), per 3 to 4 weeks went through 5 to 7 days.
In another example (for example multiple myeloma):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice; And
(2) proteoplast inhibitor (for example PS-341-Millenium) is administered twice weekly with about 1.5 milligrams/square metre amount, goes through continuous two weeks, with all withdrawal times.
In another example (for example multiple myeloma):
(1) fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, is preferably about 75 milligrams of extremely about 125 milligrams of one day administered twice, and most preferably is about 100 milligrams of one day administered twice; And
(2) Thalidomide (or relevant imide) is with the oral way administration, and its amount wherein is to take medicine continuously for about 200 to about 800 mg/day, up to recurrence or toxic till.
In example above, taxotere and cis-platinum, taxotere and carboplatin, taxol and carboplatin, or taxol and cis-platinum are preferably in administration on the same day.
The antineoplastic agent that can unite use with fpt inhibitor is:
(1) taxanes, such as taxol (Taxol _) and/or docetaxel (Taxotere _);
(2) iridium-platinum complex, for example carboplatin, cis-platinum and RP-54780;
(3) EGF inhibitor, it is an antibody, for example: HER2 antibody (trastuzumab (Herceptin for example _), Genentech company), Cetuximab (the former times monoclonal antibody is wanted in the west) (Erbitux, IMC-C225, the Imclone system), EMD72000 (MerckKGaA), anti--EFGR monoclonal antibody ABX (Abgenix), TheraCIM-h-R3 (molecular immunology center), monoclonal antibody 425 (MerckKGaA), monoclonal antibody ICR-62 (ICR, Sutton, England); Conspicuous Jim (Herzyme) (Elan medicine technology and ribose ferment medicine), PKI166 (Novartis), EKB569 (Wyeth-Ayerst), GW572016 (GIaxoSmithKline), CI1033 (Pfizer whole world research and development), trastuzumab-Mei Tan practise promise (maytansinoid) conjugate (Genentech company), Mi Tumomabai (mitumomab) (Imclone system and MerckKgaA) and MelvaxII (Imclone system and MerckKgaA);
(4) EGF inhibitor, it is a small molecules, such as tower thank weary (Tarceva) (TM) (OSI-774, OSI pharmaceuticals) and Iressa (ZD1839, AstraZeneca);
(5) VEGF inhibitor, it is an antibody, for example: rhuMAb-VEGF (Genentech company) and IMC-1C11 (Imclone system), DC101 (a kind of KDRVEGF acceptor 2 derives from the Imclone system);
(6) VEGF kinase inhibitor, it is a small molecules, such as SU5416 and SU6688 (both derive from Sugen company);
(7) estrogen receptor antagon or selective estrogen receptor modulators (SERM), for example tamoxifen, IDALL's west fen (Idoxifene), Rui Luoxi fen (raloxifene), trans-2,3-dihydro Rui Luoxi fen, lev go out western fen (Levormeloxifene), Zhuo Luoxi fen (droloxifene), MDL103,323 and Ah can must fen (acolbifene) (Schering company);
(8) antitumor nucleoside derivates, such as 5 FU 5 fluorouracil, gemcitabine (gemcitabine) or card are joined Xi Tabin (capecitabine);
(9) Ai Boxi ketone (Epothilone), such as BMS-247550 (Bristol-MyersSquibb) and EPO906 (Novartis medicine);
(10) topology isomerase inhibitors, for example open up Bo Tiken (topotecan) (GlaxoSmithKline) with camphane Pu Tuosa (camptosar) (Pharmacia);
(11) vinca alkaloids, for example (,) Na Weibin (navelbine) (Anvar and Fabre, France), vincristine(VCR) and vincaleucoblastine; And
(12) antibody, it is that α V β 3 integrates plain inhibitor, such as LM-609 (consult Clinical Cancer Research, the 6th volume, the 3056-3061 page or leaf, in August, 2000, its disclose content be and in this paper for its with reference to).
Preferred antineoplastic agent is selected from: taxol, docetaxel, carboplatin, cis-platinum, gemcitabine, tamoxifen, Herceptin (trastuzumab), Cetuximab (the former times monoclonal antibody is wanted in the west), tower are thanked weary (Tarceva), Iressa, rhuMAb-VEGF, Na Weibin (navelbine), IMC-1C11, SU5416 or SU6688.
Most preferably antineoplastic agent is selected from: taxol, docetaxel, carboplatin, cis-platinum, Na Weibin, gemcitabine or trastuzumab.
Generally speaking, when use surpassing a kind of antineoplastic agent in the inventive method the time, antineoplastic agent is with its standard dosage forms, in administration on the same day, no matter is simultaneously or continuously.For example, antineoplastic agent preferably instils by IV normally with the administration of intravenously mode, uses this area IV solution known (for example isotonic saline solution (0.9%NaCl) or dextrose solution (for example 5% dextrose)).
When using two or more antineoplastic agents, antineoplastic agent is usually in administration on the same day; But, it will be appreciated by those skilled in the art that antineoplastic agent can be in not reaching on the same day in all administrations of difference.The clinicist can use this medicament according to the dosage timetable of being advised from the antineoplastic agent person of preparation, and can adjust this timetable according to patient's demand, is basic Chu with the patient to the reaction for the treatment of for example.For example, when gemcitabine and for example cis-platinum merging use of iridium-platinum complex, during with treatment lung cancer, gemcitabine and cis-platinum are first days in treatment cycle, in giving on the same day, gemcitabine is to give separately in the 8th day then, and gives once separately at the 15th day again.
Therefore, a specific embodiments of the present invention relates to a kind of treatment method for cancer, and it comprises fpt inhibitor, Taxan and iridium-platinum complex to significant quantity on patient's administering therapeutic of this kind of needs treatment.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, it comprises fpt inhibitor, Taxan and iridium-platinum complex to significant quantity on patient's administering therapeutic of this kind of needs treatment, wherein this fpt inhibitor is administration every day, this Taxan is weekly to be administered once weekly the phase, and this iridium-platinum complex is weekly to be administered once weekly the phase.This treatment be preferably weekly the phase one to around.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, it comprises fpt inhibitor, Taxan and iridium-platinum complex to significant quantity on patient's administering therapeutic of this kind of needs treatment, wherein this fpt inhibitor is administration every day, this Taxan is weekly to be administered once in phase in per three weeks, and this iridium-platinum complex is weekly to be administered once in phase in per three weeks.This treatment is preferably weekly one to three week of phase.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, and it comprises fpt inhibitor, taxol and carboplatin to significant quantity on patient's administering therapeutic of this kind of needs treatment.Preferably, this fpt inhibitor is administration every day, and this taxol is that every circulation is administered once weekly, and this carboplatin is that every circulation is administered once weekly.This treatment be preferably weekly the phase one to around.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, and it comprises fpt inhibitor, taxol and carboplatin to significant quantity on patient's administering therapeutic of this kind of needs treatment.Preferably, this fpt inhibitor is administration every day, and this taxol is to be administered once in per three weeks of every circulation, and this carboplatin is to be administered once in per three weeks of every circulation.This treatment is preferably weekly one to three week of phase.
Nonsmall-cell lung cancer is preferably treated with the method described in the above-mentioned specific embodiments.
Another specific embodiments of the present invention relates to a kind of in the patient of needs treatment, the method of treatment nonsmall-cell lung cancer, it comprises the fpt inhibitor of significant quantity on administering therapeutic every day, the phase is weekly weekly for the carboplatin of significant quantity on the administering therapeutic, and administering therapeutic on significant quantity taxol weekly the phase weekly, wherein the treatment be every circulation give one to around.This fpt inhibitor is preferably and is administered twice every day.This carboplatin and this taxol be preferably in administration on the same day, and more preferably this carboplatin and this taxol are successive administrations, and most preferably to be this carboplatin be administration after this taxol.
Another specific embodiments of the present invention relates to a kind of in the patient of needs treatment, the method of treatment nonsmall-cell lung cancer, it comprises the fpt inhibitor of significant quantity on administering therapeutic every day, phase in per three weeks are once weekly for the carboplatin of significant quantity on the administering therapeutic, and on the administering therapeutic taxol of significant quantity once wherein treatment gave for one to three week phase in per three weeks weekly.This fpt inhibitor is preferably and is administered twice every day.This carboplatin and this taxol be preferably in administration on the same day, and more preferably this carboplatin and this taxol are successive administrations, and most preferably to be this carboplatin be administration after this taxol.
Another specific embodiments of the present invention relates to a kind of in the patient of needs treatment, the method of treatment nonsmall-cell lung cancer, it comprises uses about 50 to one day twice of about 200 milligrams of fpt inhibitor, with provide AUC be about 2 to the amount of about 8 (being preferably about 2 to about 3) use carboplatin weekly the phase weekly, the phase that reaches weekly uses about 60 to about 300 milligrams/square metre once in a week and (is preferably about 50 to 100 milligrams/square metre, more preferably about 60 to about 80 milligrams/square metre) taxol, wherein the treatment be give weekly the phase one to around.At one more preferably in the specific embodiments, this fpt inhibitor is with about 75 to about 125 milligrams amount one day administered twice, wherein about 100 milligrams one day twice be preferred.Being preferably this carboplatin and this taxol is in administration on the same day, and more preferably this carboplatin and this taxol are successive administrations, and most preferably to be this carboplatin be administration after this taxol.
In a preferred specific embodiments, the present invention relates to a kind of in the patient of needs treatment, the method of treatment nonsmall-cell lung cancer, it comprises uses about 50 to one day twice of about 200 milligrams of fpt inhibitor, to provide AUC about 2 to about 8 (to be preferably about 5 to about 8, most preferably be 6) amount use carboplatin phase in per three weeks be once weekly, and once use about 150 to about 250 milligrams/square metre weekly phase in per three weeks and (be preferably about 175 to about 225 milligrams/square metre, most preferably be 175 milligrams/square metre) taxol, wherein the treatment be to give for one to three week.At one more preferably in the specific embodiments, this fpt inhibitor is with about 75 to about 125 milligrams amount one day administered twice, wherein about 100 milligrams one day twice be preferred.Being preferably this carboplatin and this taxol is in administration on the same day, and more preferably this carboplatin and this taxol are successive administrations, and most preferably to be this carboplatin be administration after this taxol.
Other specific embodiments of the present invention relate to method for cancer described in the above-mentioned specific embodiments of treatment, and except substituting taxol and carboplatin, the taxanes and the iridium-platinum complex that are used in together in these methods are: (1) docetaxel (Taxotere _) and cis-platinum; (2) taxol and cis-platinum; And (3) docetaxel and carboplatin.In the methods of the invention, cis-platinum preferably uses to about 100 milligrams/square metre amount with about 30.In the methods of the invention, docetaxel preferably uses to about 100 milligrams/square metre amount with about 30.
In another specific embodiments, the present invention relates to a kind of treatment method for cancer, it comprises to the fpt inhibitor of significant quantity on patient's administering therapeutic of this kind of needs treatment, Taxan and as the EGF inhibitor of antibody.Employed Taxan is preferably taxol, and the EGF inhibitor is preferably HER2 antibody (Herceptin (trastuzumab) more preferably) or Cetuximab (Cetuximab), and most preferably is to use trastuzumab.Treatment length, and the amount and the administration of fpt inhibitor and Taxan are all as mentioned described in the specific embodiments.The EGF inhibitor, it is an antibody, it is administered once weekly in one week of phase, and preferred and Taxan is in administration on the same day, and be more preferably and the Taxan successive administration.For example, trastuzumab is the load scale of construction administration with about 3 to about 5 milligrams/square metre (being preferably about 4 milligrams/square metre), then with about 2 milligrams/square metre maintenance dose administration, weekly the phase weekly, all the other that go through this treatment cycle are (this cycle often was 1 to 4 week) partly.Cancer through treatment is preferably mammary cancer.
In another specific embodiments, the present invention relates to a kind of treatment method for cancer, it comprises the following material to significant quantity on patient's administering therapeutic of this kind of needs treatment:
(1) fpt inhibitor;
(2) Taxan; And
(3) antineoplastic agent is selected from:
(a) EGF inhibitor, it is a small molecules;
(b) VEGF inhibitor, it is an antibody; Or
(c) VEGF kinase inhibitor, it is a small molecules.
Preferably use Taxan taxol or docetaxel.Antineoplastic agent is preferably selected from: tower is thanked weary (Tarceva), Iressa, rhuMAb-VEGF, SU5416 or SU6688.The amount and the administration of treatment length and fpt inhibitor and Taxan, all person described in the specific embodiments as mentioned.The VEGF kinase inhibitor is an antibody, and phase gives once weekly weekly usually for it.EGF and VEGF inhibitor are small molecules, and it gives weekly usually every day phase.The VEGF inhibitor is an antibody, its preferably with Taxan in giving on the same day, and be more preferably and Taxan administration simultaneously.When micromolecular EGF inhibitor or micromolecular VEGF inhibitor are with Taxan during in administration on the same day, this administration preferably with Taxan administration simultaneously.EGF or VEGF kinase inhibitor generally are to about 500 milligrams/square metre amount administration with about 10.Cancer through treatment is preferably nonsmall-cell lung cancer.
In another specific embodiments, the present invention relates to a kind of treatment method for cancer, it comprises fpt inhibitor, antitumor nucleoside derivates and iridium-platinum complex to significant quantity on patient's administering therapeutic of this kind of needs treatment.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, it comprises fpt inhibitor, antitumor nucleoside derivates and iridium-platinum complex to significant quantity on patient's administering therapeutic of this kind of needs treatment, wherein this fpt inhibitor is administration every day, this antitumor nucleoside derivates weekly the phase be administered once weekly, and this iridium-platinum complex the phase is administered once weekly weekly.Though this treatment can be weekly the phase one to around, this treatment is preferably weekly one to seven week of phase.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, it comprises fpt inhibitor, antitumor nucleoside derivates and iridium-platinum complex to significant quantity on patient's administering therapeutic of this kind of needs treatment, wherein this fpt inhibitor is administration every day, this antitumor nucleoside derivates is weekly to be administered once weekly the phase, and phase in per three weeks are administered once weekly to reach this iridium-platinum complex.Though this treatment can be weekly the phase one to around, this treatment is preferably weekly one to seven week of phase.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, and it comprises fpt inhibitor, gemcitabine and cis-platinum to significant quantity on patient's administering therapeutic of this kind of needs treatment.Preferably, this fpt inhibitor is administration every day, this gemcitabine weekly the phase be administered once weekly, and this cis-platinum the phase is administered once weekly weekly.This treatment is preferably weekly one to seven week of phase.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, and it comprises fpt inhibitor, gemcitabine and cis-platinum to significant quantity on patient's administering therapeutic of this kind of needs treatment.Preferably, this fpt inhibitor is administration every day, and this gemcitabine is weekly to be administered once weekly the phase, and this cis-platinum is weekly to be administered once in phase in per three weeks.This treatment was preferably for one to seven week.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, and it comprises fpt inhibitor, gemcitabine and carboplatin to significant quantity on patient's administering therapeutic of this kind of needs treatment.Preferably, this fpt inhibitor is administration every day, and this gemcitabine is weekly to be administered once weekly the phase, and this carboplatin is weekly to be administered once weekly the phase.This treatment is preferably weekly one to seven week of phase.
Another specific embodiments of the present invention relates to a kind of treatment method for cancer, and it comprises fpt inhibitor, gemcitabine and carboplatin to significant quantity on patient's administering therapeutic of this kind of needs treatment.Preferably, this fpt inhibitor is administration every day, and this gemcitabine is weekly to be administered once weekly the phase, and this carboplatin is weekly to be administered once in phase in per three weeks.This treatment is preferably weekly one to seven week of phase.
Nonsmall-cell lung cancer is preferable in the above-mentioned specific embodiments, treats in the method for using gemcitabine.
In the specific embodiments of above-mentioned use gemcitabine, fpt inhibitor and iridium-platinum complex are to carry out administration as mentioned described in the specific embodiments of using taxanes.Gemcitabine is to about 1250 milligrams/square metre amount administration with about 500.Gemcitabine preferably with iridium-platinum complex in administration on the same day, and more preferably with the iridium-platinum complex successive administration, and most preferably to be gemcitabine be administration after the iridium-platinum complex.
Another specific embodiments of the present invention relates to a kind of in the patient of needs treatment, the treatment method for cancer, it comprises uses fpt inhibitor and antineoplastic agent to this patient, and described antineoplastic agent is selected from: (1) EGF inhibitor, it is an antibody, (2) EGF inhibitor, it is a small molecules, (3) VEGF inhibitor, it is an antibody, and (4) VEGF kinase inhibitor, it is a small molecules, all as above-mentioned.This treatment is one to seven week of phase weekly, and be generally weekly the phase one to around.Fpt inhibitor is with as mentioned about the described same way as administration of other specific embodiments of the present invention.The small molecules antineoplastic agent is administration every day normally, and the antibody antineoplastic agent normally the phase is administered once weekly weekly.Antineoplastic agent is preferably selected from: He Xibai booth, Cetuximab, tower are thanked weary, Ai Ruisha, rhuMAb-VEGF, IMC-1C11, SU5416 or SU6688.Preferably treat nonsmall-cell lung cancer.
In specific embodiments of the present invention, wherein be to use iridium-platinum complex and at least a other antineoplastic agents, and these medicines are successive administrations, iridium-platinum complex generally in other antineoplastic agents by administration after the administration.
Other specific embodiments of the present invention except use fpt inhibitor and antineoplastic agent in above-mentioned specific embodiments, comprise the radiation to significant quantity on patient's administering therapeutic.Radiation is technology and the doubtful case administration known according to those skilled in the art.
Another specific embodiments of the present invention relates to a kind of pharmaceutical composition, and it comprises at least two kinds of different antineoplastic agents, and the pharmaceutically acceptable carrier that supplies intravenous administration to use.This pharmaceutically acceptable carrier is preferably normal isotonic saline solution (0.9%NaCl) or dextrose solution (for example 5% dextrose).
Another specific embodiments of the present invention relates to a kind of pharmaceutical composition, and it comprises the different antineoplastic agents with at least two kinds of fpt inhibitor, and the pharmaceutically acceptable carrier that supplies intravenous administration to use.This pharmaceutically acceptable carrier is preferably normal isotonic saline solution (0.9%NaCl) or dextrose solution (for example 5% dextrose).
Another specific embodiments of the present invention relates to a kind of pharmaceutical composition, and it comprises fpt inhibitor and at least a antineoplastic agent, and the pharmaceutically acceptable carrier that supplies intravenous administration to use.This pharmaceutically acceptable carrier is preferably normal isotonic saline solution (0.9%NaCl) or dextrose solution (for example 5% dextrose).
In the method for treatment specific embodiments, and in the pharmaceutical composition specific embodiments, fpt inhibitor is preferably the formula of being selected from 1.4,1.4D, 1.4E, 1.4F, 1.5,1.5A, 1.6,1.6A, 1.7 and the compound of 1.7A compound.
It will be understood by those skilled in the art that the compound (medicine) that is used in the inventive method,, can derive from the preparation merchant by pharmaceutical composition (formulation), and be used in these compositions the clinicist.Therefore, enumerating of compound in aforesaid method or classes of compounds can substitute with enumerating of the pharmaceutical composition that comprises this specific compound or classes of compounds.For example, relate to the specific embodiments for the treatment of the cancer method, it comprises fpt inhibitor, Taxan and iridium-platinum complex to significant quantity on patient's administering therapeutic of this kind of needs treatment, in its scope, comprise a kind of treatment method for cancer, it comprises a kind of pharmaceutical composition that comprises fpt inhibitor (1.0) to significant quantity on patient's administering therapeutic of this kind of needs treatment, a kind of pharmaceutical composition that comprises Taxan, and a kind of pharmaceutical composition that comprises iridium-platinum complex.
The actual dose that is adopted can change according to patient's requirement and by the seriousness of treatment symptom.To the decision of the suitable dosage of particular condition in those skilled in the art's limit of power.
Using the amount and the frequency of fpt inhibitor and antineoplastic agent, is to adjust according to the judgement of being responsible for clinical teacher (doctor), considers some factors, such as patient's age, symptom and size, and by the seriousness of treatment cancer.
Antineoplastic agent can be according to this area treatment doubtful case known administration.It is evident that for those skilled in the art the administration of antineoplastic agent can be according to by the cancer of being treated and antineoplastic agent the known action of this disease being changed.And, according to clinicist's knowledge, treatment doubtful case (for example dosage of administration and number of times) can in view of institute's administering therapeutic agent to the effect that the patient found, and the reaction of institute's drug treatment agent being found in view of cancer and changing.
Initial administration can have been set up doubtful case and implemented according to known in the art, and the basic Chu that act as to be found then can be revised dosage, pattern and the administration number of times of administration by the clinicist.
The specific selection of antineoplastic agent is to decide with suitably treating doubtful case according to the diagnosis of being responsible for the doctor and to the judgement of patient's symptom.
During the treatment doubtful case, the decision of the repetition number of order of administration and antineoplastic agent administration after by the assessment of treatment cancer and patient's symptom, is well in the ken of skilled practitioners.
Therefore, rule of thumb with knowledge, when treatment is carried out, carry out the doctor and can revise in order to use each doubtful case of antineoplastic agent according to the needs of individual patient.All this kind corrections all within the scope of the invention.
Be responsible for the clinicist, in whether judgement treats under the dosage of being used effectively, it is the general health of considering the patient, and clearer and more definite symptom, for example cancer related symptoms (for example pain, cough (for lung cancer) and (for lung cancer) short of breath) alleviates, the inhibition of tumor growth, the actual inhibition of dwindling or shifting of tumour.The big I of tumour is measured by standard method, such as radiologic investigation, for example CAT or MRI scanning, and can use continuous measure, to judge whether growth of tumor has been slowed down or even to reverse.Alleviating of disease related symptom such as pain, and the improvement on whole symptom also can be in order to help to judge the validity of treatment.
Chemotherapeutic
Can be used as the classes of compounds that chemotherapeutic (antineoplastic agent/microtubule influences agent) uses, include but not limited to: alkylating agent, metabolic antagonist, natural product and derivative thereof, hormone and steroid (comprising synthetic analogues) and synthetic.Examples of compounds in these kinds is shown in hereinafter.
Alkylating agent (comprising nitrogen mustards, ethyliminum derivative, alkyl sulfonic ester, nitrosourea and triazene class): NSC-34462, chlormethine, endoxan (Cytoxan _), Yi Fasi acid amides (ifosfamide), phenyalamine mustard, Chlorambucil (Chlorambucil), pipobroman, triethylene-trimeric cyanamide, triethylene sulfo-phosphamidon, busulfan (Busulfan), Carmustine, lomustine, strepto-nitroso-group element, dacarbazine and sky Lip river acid amides (Temozolomide) not.
Metabolic antagonist (comprising antifol, pyrimidine analogue, purine analogue and adenosine deaminase inhibitors): methotrexate, 5 FU 5 fluorouracil, floxuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, not reach Rabin (Fludarabine) phosphoric acid salt, penta holder system rhzomorph (pentostatin) and gemcitabine.
Natural product and derivative thereof (comprising vinca alkaloids, antitumor antibiotics, ferment, lymphokine and epipodophyllotoxin): vincaleucoblastine, vincristine(VCR), Vincamine, bleomycin, Da Keting mycin, daunorubicin, restrain the Suo Hong rhzomorph more, show red rhzomorph, according to reach red rhzomorph, (taxol can Taxol for taxol _Commercial and get, and be described in greater detail in hereinafter title in the merogenesis of " microtubule influences agent "), D51-7059 (for example taxotere (taxotere)), mithramycin, deoxidation formycin, Mitomycin-C, altheine enzyme, Interferon, rabbit (especially IFN-a), clothing holder glucosides (etoposide) and day Buddhist nun's glycosides altogether.
Hormone and steroid (comprising synthetic analogues): the female alcohol of 17 alpha-acetylenes, diethylstilbestrol, testosterone, prednisone, FL, Zhuo Moshitan ketone (Dromostanolone) propionic salt, the testis lactones, megestrol acetate, tamoxifen, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium, female Maas spit of fland (estramustine), the Zytron acetic ester, stay general lactone (leuprolide), not as acid amides (flutamide), Tuoli rice fen (toremifene), Zhuo draws ground this (Zoladex).
Synthetic (comprise inorganic complex, such as platinum coordination complex): cis-platinum, carboplatin, hydroxyurea, A Musa element (amsacrine), procarbazine, mitotane, silk split flavones (mitoxantrone), L-tetramisole and altretamine.
Other chemotherapeutics comprise that also (Navelbene), CPT-11, At history azoles (Anastrazole), row arrange azoles (letrazole), Ka Peitabin than (Capecitabinbe), Rui Luosha fen (Reloxafine) and Zhuo Luosha fen (Droloxafine) to Na Wei.
Special good antineoplastic agent is selected from endoxan, 5 FU 5 fluorouracil, sky not Lip river acid amides (temozolomide), vincristine(VCR), cis-platinum, carboplatin and gemcitabine.Most preferably antineoplastic agent is selected from gemcitabine, cis-platinum and carboplatin.
The safe and effective medication of most these chemotherapeutics, for those skilled in the art known.In addition, its administration is to be described in the normative document.For example, the administration of many chemotherapeutics is to be described in " doctor's table is gone up bibliography " (PDR), for example 1996 editions (medical economics company, Montvale, NJ07645-1742, USA); Its disclose content be and in this paper for its reference.
Microtubule influences agent
The microtubule of Shi Yonging influences agent (for example taxol, D51-7059 or like taxol compound) for can the mitotic compound of interference cell in this article, and meaning is that it has the antimitotic effect, and its mode is influence microtubule to form and/or act on.This kind medicament can be microtubule tranquilizer for example maybe can disintegrate the medicament that microtubule forms.
The microtubule that can be used among the present invention influences agent, by those skilled in the art known, and include but not limited to other colchicine (NSC406042), Harry chrondroitin B (NSC609395), colchicine (NSC757), colchicine derivative (for example NSC33410), Duola make rhzomorph 10 (NSC376128), maytansine (NSC153858), sharp sit plain (rhizoxin) (NSC332598), taxol (Taxol _NSC125973), D51-7059 (taxotere for example, NSC608832), sulfenyl colchicine (NSC361792), trityl aminothiopropionic acid (NSC83265), vincaleucoblastine vitriol (NSC49842), leucocristine sulfate (NSC67574), Ai Pu Shillong A, Ai Boxi ketone and enlightening this can get lactone (discodermolide) and (consult, Serve (1996) Science, 274:2009), female Maas spit of fland (estramustine), Nuo Keda azoles (nocodazole), MAP4 etc.The example of this kind medicament also is described in science and the patent documentation, consults, for example Bulinski (1997) J.CellSci.110:3055-3064; Panda (1997) Proc.Natl.Acad.Sci.USA94:10560-10564; Muhlradt (1997) CancerRes.57:3344-3346; Nicolaou (1997) Nature387:268-272; Vasquez (1997) Mol.Biol.Cell.8:973985; Panda (1996) J.Biol.Chem.271:29807-29812.
Particularly preferred medicament is for having like the active compound of taxol.It includes but not limited to taxol and D51-7059 (like taxol compound) and analogue.Taxol and derivative thereof (for example taxol (taxol) with taxotere (taxotere)) are commercially available and get.In addition, prepare the method for taxol and D51-7059 and analogue, (consult, for example United States Patent (USP) case number: 5,569,729 by those skilled in the art are known; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488, l16; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; And 5,296,506).
More clear and more definite speech, " taxol " speech of Shi Yonging in this article, being meant can Taxol _(the NSC number: 125973) commercial and medicine.Taxol _Can become the microtubule fasolculus of stabilization that can not reassemble into mitotic appropriate configuration via strengthening tubulin polymerization partly, duplicate and suppress eukaryotic cell.In many adoptable chemotherapeutic agents, taxol has produced importance, because of it has the anti-effect of stubborn tumour of opposing medicine in clinical trial, comprise ovary and breast tumor (Hawkins (1992) oncology, 6:17-23, Horwitz (1992) Trends Pharmacol.Sci.13:134-146, Rowinsky (1990) J.Natl.Canc.Inst.82:1247-1259).
Other microtubules influence agent and can use one of many this kind detections known in the art to assess, for example semi-automatic the detection, it is the tubulin polymerization activity of tolerance paclitaxel analogs, and associating use cell detection is with the possibility (consulting Lopes (1997) CancerChemother.Pharmacol.41:37-47) of measuring the cell in these compounds block mitotic division.
Whether generally speaking, the activity of testing compound is via cell is contacted with this compound, and measure the cell cycle and disintegrated, and particularly records through the inhibition of mitotic division situation.This kind inhibition can mediate via disintegrating of mitotic division element, and for example normal spindle body structure disintegrates.Wherein the interrupted cell of mitotic division can be made characterized (for example chromosome number of microtubule tightness, increase etc.) by reformed morphology.
Have the active compound of possibility tubulin polymerization, can be in vitro screening.For example, these compounds are anti-WR21 cells (derived from clone 69-2wap-ras mouse) of cultivating, and about outgrowth inhibition and/or the morphocytology through changing, particularly the microtubule tightness is screened.Then, the in vivo screening of positive test compounds can use the nude mouse that has the WR21 tumour cell to implement.The detailed doubtful case of this screening method is by Porter (1995) Lab.Anim.Sci., and 45 (2): 145-150 describes.
Other SCREENED COMPOUND to be obtaining the active method of being wanted, by those skilled in the art known.On the typical case, this kind detection relates to suppress the detection of microtubule assembling and/or decomposition.The detection of microtubule assembling is by people (1974) J.Molec.Biol. such as for example Gaskin, and 89:737-758 describes.United States Patent (USP) 5,569,720 also provide about having in vitro with in vivo detecting like the active compound of taxol.
Use the method that above mentioned microtubule influences agent about safe and effective, for those skilled in the art known.In addition, its administration is to be described in the normative document.For example, the administration of many chemotherapeutics is to be described in " doctor's table is gone up bibliography " (above citation).
General preparation feedback scheme
Can adopt following method with the preparation The compounds of this invention.
The pyridyl tricyclic compound
It will be understood by those skilled in the art that the The compounds of this invention with formula 1 expression, is N or N one of among a, b, c or the d wherein +-O -, can be according to the preparation of reaction scheme hereinafter:
Reaction scheme 1:
Figure A0380472002671
5-bromine tricyclic compound 1b's is synthetic, be by end of the bridge alkene 1a (J.MedChem (1998), 41,1561-1567) beginning in the trifluoromethanesulfonic acid medium, is handled it with dibromodimethyl hydantoin.Exist down in suitable secondary amine, further handle this ethylene bromide, obtain the enamine affixture that 5-and 6-replace with potassium tert.-butoxide.Y 1Expression-CH 2-,-O-or-NH-.Work as Y 1During for NH (piperazine situation), can use standard method to carry out acylation, sulfoacylation and acid amides and form.Under proper temperature, handle these amine affixtures with HCl (aqueous solution), can form 5 and 6 azepine ketones respectively, form 1f and 1e.
Reaction scheme 2:
(wherein Rx represents R 9)
In the situation of the secondary eneamines of needs, as institute's general introduction in the reaction scheme 2, utilization is synthesized by 1f and 1e azepine ketone.Therefore, in the DeanStark device, exist down, make suitable ketone and amine in reflux in toluene in tosic acid.
Reaction scheme 3:
(wherein R " expression H or alkyl (for example methyl and ethyl)
3-carbon is analogue synthetic at interval, can such as reaction scheme 3 general introduction and making.Therefore, make three cyclic vinyl bromide 1b carry out the Heck type reaction, use ethyl propenoate, and pass through Pd 0Catalysis obtains the unsaturated ester 3a of alpha-beta.The reductive action of conjugated double bond is to use cupric chloride-sodium borohydride reduction reagent to carry out.Use lithium aluminium hydride, make this ester further be reduced into alcohol.This alcohol with methylsulfonyl chloride, is handled in suitable non-protonic solvent, then, generated desired imidazoles target compound with suitable sodium salt displacement.In most situation, the separation of isomer is to reach this moment.R at 3e 8Group is in the situation of Boc group, uses the HCl-dioxane to remove protection, obtains the hydrochloride of amine.Use standard chemical, make these amines change into ureas, amino formate, sulfonamides and amides.
It will be understood by those skilled in the art that to change among the 3e in 3d when in reaction scheme 3, use metal hydride, such as during NaH, the reduction of the two keys of C5-C6 can take place.This is schematically illustrated among the preparation embodiment 59 step B.
Reaction scheme 4:6-replaces the preparation of carbon analogue
Figure A0380472002691
(wherein R " expression H or alkyl (for example methyl and ethyl))
6-replaces the preparation of imidazolium compounds at interval of 3-carbon, is undertaken by general introduction in the reaction scheme 4.The mixture of ketone 1f and 1i is handled with N-phenyl trifluoromethanesulfonate methylsulfonyl imines, and 5 with the separable mixture of the triflated compound of 6-three ring-types.Use as be summarized in the reaction scheme 3 about the described similar doubtful case of 5-bromine tricyclic compound, make 6-triflate affixture change into desired 3-carbon analogue at interval.
Synthesizing of reaction scheme 5:2-carbon spacer analogue
Figure A0380472002701
(wherein R ' expression H or alkyl (for example methyl and ethyl))
Two kinds of carbon at interval analogue be such as in the reaction scheme 5 general introduction and making.Therefore, make triflate 4b carry out the Stille chemical treatment, by reacting, through suitable Pd with stannic acid tributyl vinyl acetate 0Catalysis obtains three cyclic vinyl compound 5b.2-carbon compartmentation compound is via handling this tricyclic compound with suitable imidazoles and obtain, and this imidazoles is put in the sealed tube in advance, handles with Buli-THF, and refluxes down at 120 ℃.Further functionalization is to carry out as mentioned before.The suberane compound is to make in a similar manner.
Reaction scheme 6:
Reaction scheme 6 is explanation phthaloyl imino displacements through methanesulfonates, is the hydrazine hydrolysis of phthaloyl imino part then, to prepare the method for amine 6b.Amine 6b is changed into have acyl group, the target compound of alkylsulfonyl, carbamyl and urea functional group.
Reaction scheme 7
Figure A0380472002712
Lactan 7a can such as in the reaction scheme 7 general introduction, by with bromobutanoylchloride reaction, 6b makes by amine.
Reaction scheme 8: the preparation of ring ureas
Figure A0380472002721
The ring urea can by to encircle the salt processing of urea 8a, be made by the methanesulfonates above as institute's general introduction in the reaction scheme 8.
Reaction scheme 9:5-replaces the preparation of propanoic derivatives:
Figure A0380472002722
Derive from the at interval amides of carboxylic acid 9a and 9c of 3-carbon, can such as in the reaction scheme 9 general introduction, the use doubtful case that DEC-HOBT mediated or make by suitable acyl chlorides.
Reaction scheme 10:
The preparation of end of the bridge diethylenediamine compound is to be begun by methanesulfonates aa, the piperazine reaction that itself and CBZ-are protected.Then, remove the BOC group, and make formed amine 10c through suitably functionalized.Removing of the CBZ group of piperazine is to use TMSI to reach.
Methanesulfonates aa makes in the following manner, at first makes the compound H of autoreaction scheme 14 to use Pd in methyl alcohol 0, triphenyl phosphine, carbon monoxide, DBU, carry out carbonylation, and the ethoxycarbonyl product.Then, make the reduction of ethoxycarbonyl product, obtain formed alcohol with lithium aluminium hydride.Use methylsulfonyl chloride and triethylamine, make this alcohol change into methanesulfonates aa.
Imidazoles-3-methylene radical-piperidines that reaction scheme 11:C-replaces
In inert solvent, such as in toluene or the tetrahydrofuran (THF), make compound 12a reduction, after acid treatment, obtain 12b with DIBAL.Exist down in ethyl-magnesium-bromide, in the solvent of methylene dichloride for example, under room temperature, handle 12b, produce affixture 12c with the imidazoles iodide of suitable replacement and tritylation.Removing of hydroxyl is to use methylsulfonyl chloride, Tosyl chloride or thionyl chloride, via making hydroxyl change into suitable leavings group, such as methanesulfonates, tosylate or halogenide, then use suitable alkali, for example (,) triethylamine, remove, obtain 12e.With acid, for example (,) trifluoracetic acid or hydrochloric acid, remove trityl, obtain double bond compound 12f, use suitable catalyzer then, such as platinum oxide, under 1 to 55psi hydrogen, in appropriate solvent such as ethanol, make its hydrogenation, obtain desired product 12g.
Perhaps, suitably alkali, such as lithium hydroxide makes ester 12a saponification, obtains sour 12h.Make sour 12h change into " Weinreb acid amides ", then exist down, in the solvent of methylene dichloride for example, under room temperature in ethyl-magnesium-bromide, with the reaction of the imidazoles iodide of suitable replacement and tritylation, produce affixture 12c (be shown in hereinafter reaction scheme 12 in).
Reaction scheme 12:
Reaction scheme 12a:
Figure A0380472002781
The compound of Class1 2L is to make shown in above.The oxygenizement of oxy-compound 12c can DessMartin be crossed iodine alkane (periodinane) and is reached, and obtains 12j.The Yu Geshi reagent react obtains 12k.Under standard conditions referred to above, remove trityl, obtain desired compound 12L.
The single methylene radical end of the bridge of the imidazoles compound that reaction scheme 13:C-replaces
Single methylene radical end of the bridge C-imdazole derivatives (13c) is to make shown in above.At first make compound 13a change into bromide 13b.Handle compound 13b with C-copper imidazolate hydrochlorate (system is from corresponding iodine imidazoles), produce affixture 13c.
Reaction scheme 14: the preparation of single methylene radical piperazine
In the solvent of methylene dichloride for example, under high temperature, such as 80-100 ℃, with bromide reagent, such as NBS, with a small amount of activator, such as benzoyl peroxide, make ketone A bromination, and dibromo compound B.
Make dibromo compound B and alkali, for example (,) DBU, in solvent, for example (,) methylene dichloride, react to the temperature of room temperature in 0 ℃, obtain vinyl bromination thing C and D.Via chromatogram, such as the hurried formula chromatogram of silica gel is used solvent mixture, such as vinyl acetic monomer and hexane, separates with these vinyl bromination things.Perhaps, vinyl bromination thing C and D can be from solvents, such as methylene dichloride, via Crystallization Separation.
Figure A0380472002802
Use reductive agent, such as NaBH 4, in solvent, such as in methyl alcohol or the ethanol, 0 ℃ to the temperature of room temperature, make the ketone group of isolating vinyl bromination thing C and D be reduced into its corresponding alcohols E and F.
Use reagent, such as SOCl 2, in solvent, such as in the methylene dichloride, contain alkali, such as 2, the 6-lutidine makes the alcohol functional group that forms of E and F change into leavings group, such as halogenide, and carries out this reaction at 0 ℃ to room temperature.Make formed middle halogenide, need not purifying, with piperazine or piperazine through protecting, such as the BOC-piperazine, in solvent such as methylene dichloride, under room temperature, react, obtain intermediate G and H.
Under the temperature of the pressure of about 100psi and 80 ℃ to 100 ℃, use catalyzer, such as PdCl 2With triphenyl phosphine, in toluene, and contain DBU, and for example in the alcohol of methyl alcohol, make vinyl halide intermediate carbonylation with CO gas.If use methyl alcohol, then obtain methyl esters I and J.
Make the ester functional group of I and J be reduced into the methylol functional group of K and L.This can directly reach in the following manner, at first removes protectiveness BOC group with TFA or HCl-dioxane, with reductive agent such as DIBAL-H reduction, then introduces the BOC group again with two carbonic acid, two-tert-butyl ester then.Perhaps, make the hydrolysis of ester functional group, then neutralize with citric acid with LiOH and water.Then, make formed carboxylic acid change into the functional group that easily is reduced, such as mixed acid anhydride or acylimidazole.This is to reach in the following manner, makes acid of formed carbocyclic ring family and chloro-formic ester reaction, forming mixed acid anhydride, or with the carbonyl dimidazoles reaction, to form acylimidazole (Synlett. (1995), 839).Make formed activating carboxy acid, in solvent such as methyl alcohol, ethanol or the THF aqueous solution, use NaBH 4Reduction.
Figure A0380472002821
Make the hydroxy functional group of K and L change into leavings group, such as methanesulfonates, or aromatic yl sulphonate, such as tosylate, its mode is and suitable SULPHURYL CHLORIDE, reacts in the methylene dichloride that contains alkali such as triethylamine.This sulphonate leavings group can be by nucleophilic reagent such as amine displacement.Nucleophilic reagent (Nuc in hereinafter structure O and P) also can be alkaline heterocyclic, such as imidazoles or substituted imidazoles.In the situation of imidazoles, the negatively charged ion of imidazoles is at first to form in DMF with NaH, then with above-mentioned sulphonate reaction.Replace this sulphonate with nucleophilic reagent; obtain O and P, it can be converted to The compounds of this invention 1.0, and its mode is at first to remove the BOC protecting group; mat this area method known forms desired acid amides, urea, carbamate or sulphonamide on formed amine then.
Reaction scheme 15: the preparation of single methylenepiperidines
Figure A0380472002831
Under the temperature of the pressure of about 100psi and 80 ℃ to 100 ℃, use catalyzer, such as PdCl 2With triphenyl phosphine, in toluene, and contain DBU, and for example in the alcohol of methyl alcohol,, make vinyl halide or trifluoromethanesulfonic acid vinyl acetate intermediate A with CO gas 1With B 1(reaction scheme 10) carbonylation.If use methyl alcohol, then obtain methyl esters C 1With D 1As the same procedure of reaction scheme 14, make intermediate C according to basically 1With D 1Reaction, intermediate I 1With J 1(consulting hereinafter reaction scheme 15a) also is to send out this, produces formula 1.0 compounds of the present invention.
Reaction scheme 15a:
Perhaps, intermediate A 1With B 1Can with tin vinyl ether E 1, in PdCl 2Exist down, press Tetrahedron, (1991), reaction described in 47,1877 produces vinyl ether F 1With G 1(reaction scheme 15a).Make F 1With G 1Leave standstill, up to aldehyde can see by NMR and till (at least two weeks), then with Hg (OAc) 2, KI, then and NaBH 4J.Chem.Soc. press in reaction, PerkinTrans., (1984), and 1069 and Tet.Lett., carry out described in 6331 (1988), generation mixture H 1, I 1With J 1And K 1As the same procedure of reaction scheme 14, make intermediate H according to basically 1With J 1Separate and reaction intermediate K 1With L 1Also be so, produce formula 1.0 compounds of the present invention.
H 1：n＝1??????????????????????????????????????????????????J 1：n＝1
I 1：n＝2??????????????????????????????????????????????????K 1：n＝2
It will be understood by those skilled in the art that use for example has reaction scheme 11,12 with the reactant of lower section (being relevant to formula 1.0), 12a, 13,14,15 and 15a
With
Figure A0380472002854
Also for having typical example with the reactant of lower section:
Figure A0380472002862
(being relevant to formula 1.1 compounds).
Reaction scheme 16: the branch on methene chain
(wherein R represents R 8, and R " expression R 10)
In reaction scheme 16, have substituent compound along chain, can begin to synthesize with the ethyl propenoate derivative that replaces.Add imidazoles along alkene, then reduction obtains terminal olefin, can under the Heck reaction conditions it be added with in the vinyl bromination thing through suitably replacing.The selective reduction of disubstituted olefin obtains saturated derivatives.
Reaction scheme 17:C-banded imidazoles
Figure A0380472002881
(wherein R represents R 8)
In reaction scheme 17, C-links synthesizing of imidazoles, is to carry out with the Heck reaction of suitable vinyl bromination thing through the vinyl imidazole that suitably replaces.The selective reduction of the disubstituted olefin that forms obtains target compound.Can carry out similar approach with different N-substituted imidazoles, and get N-alkyl imidazole derivative.
The suberyl compound
It will be understood by those skilled in the art that wherein a, b, c and d are that (or in formula 1.1, a, b, c and d are CR to C with the The compounds of this invention of formula 1.0 expressions 1) can make according to reaction scheme 18:
Reaction scheme 18: the preparation of octanedioyl analogue
Three cyclic vinyl bromide azepine ketone 4b are by people such as Rupard (J.Med.Chem.1989,32,2261-2268) described making.It is with NaBH that ketone is reduced into pure 4c 4Carry out.Make alcohol change into muriate 4d, handle with N-methyl piperidine Grignard reagent then, obtain piperidine derivative 4e.Demethylation is with Vinyl chloroformate, then acid hydrolysis, and follow-up derivation effect (meaning is sulfoacylation, acylation and carbonylation etc.) and reaching.Have the imidazoles compound partly that 3-carbon replaces on suberane three ring ends of the bridge, its preparation is to carry out with the similar fashion described in the reaction scheme 3.
Reaction scheme 19:
Figure A0380472002901
Reaction scheme 20:
Reaction scheme 21:
Figure A0380472002921
Isomer 1: isomer 2
(isomer 1): the ratio of (isomer 2) is about 10: 1
Be substituted the preparation of 5-ethanoyl-imidazoles
Figure A0380472002932
Reaction scheme 22:
Figure A0380472002933
* chiral centre, chemical formulation isomer 1 or isomer 2
Reaction scheme 23:
* chiral centre, chemical formulation isomer 1 or isomer 2
* chiral centre, chemical formulation isomer 1 or isomer 2,
Wherein the isomer 1 of amine is the isomer 1 that derives from trinitride, and the isomer 2 of amine is the isomer 2 that derives from trinitride
Reaction scheme 24:
Figure A0380472002961
* chiral centre, chemical formulation isomer 1 or isomer 2,
Wherein 1022 isomer 1 is the isomer 1 that derives from initial amine, and 1022 isomer 2 is the isomer 2 that derive from initial amine
Make each isomer (isomer 1 and isomer 2) and acyl chlorides or anhydride reaction of initial amine, obtain amido, obtain urea with isocyanic ester, obtain carbamate with the chlorine carbonic ether, obtain sulphonamide with SULPHURYL CHLORIDE, in appropriate solvent, such as methylene dichloride, and equivalent alkali, such as triethylamine, obtain desired product compound 1020.Then, compound 1020 can be handled with trifluoracetic acid, be obtained compound 1021.Then can make compound 1021 and acyl chlorides or anhydride reaction, obtain amido, obtain urea with isocyanic ester, obtain carbamate with the chlorine carbonic ether, obtain sulphonamide with SULPHURYL CHLORIDE, in appropriate solvent, such as methylene dichloride, and equivalent alkali, such as triethylamine, obtain desired product compound 1022.
Reaction scheme 25:
* chiral centre, chemical formulation isomer 1 or isomer 2
Reaction scheme 26:
* chiral centre, chemical formulation isomer 1 or isomer 2
Reaction scheme 27:
Figure A0380472002991
* chiral centre, chemical formulation isomer 1 or isomer 2
Reaction scheme 28:
Figure A0380472003001
* chiral centre, chemical formulation isomer 1 or isomer 2
Reaction scheme 29:
Figure A0380472003011
* chiral centre, chemical formulation isomer 1 or isomer 2
For obtaining to have R 9bThe compound of group, make amine (initial reactant) and acyl chlorides or anhydride reaction, obtain amido, obtain urea, obtain carbamate with chloro-formic ester with isocyanic ester, or obtain sulphonamide with SULPHURYL CHLORIDE, in appropriate solvent, such as methylene dichloride, and equivalent alkali, for example triethylamine has the R that wanted with acquisition 9bSubstituent compound.Then, can be with R 9bThe compound that replaces is handled with trifluoracetic acid, removes the BOC group, and must have the piperidine compounds that is not substituted nitrogen.For introducing desired R 8Group, can make and have piperidine compounds and acyl chlorides or the anhydride reaction that is not substituted nitrogen, obtain amido, obtain urea, obtain carbamate with chloro-formic ester with isocyanic ester, or obtain sulphonamide with SULPHURYL CHLORIDE, in appropriate solvent, such as methylene dichloride, and equivalent alkali, for example triethylamine obtains to have the R that wants 8Substituent compound.
Reaction scheme 30
Wherein " IM " is illustrated in Compound C O (IM) 2In imidazolyl.
Reaction scheme 31
R wherein 8Group is to use the corresponding isocyanic ester of desiring to be connected group, chloro-formic ester, SULPHURYL CHLORIDE or acyl chlorides to connect, and R wherein 9bGroup is to use corresponding isocyanic ester, chloro-formic ester, SULPHURYL CHLORIDE or the acyl chlorides of desiring to be connected group to connect.
The compounds of this invention is to be schematically illustrated among the following embodiment, the scope of content that it should not be interpreted as having limited the disclosure.Within the scope of the present invention replacement mechanism approach and similar structures to those skilled in the art, can be apparent.The compounds of this invention can be made according to described method herein and in the method described in the WO02/18368A1 of bulletin on March 7th, 2002.
Preparation embodiment 2
Steps A
Figure A0380472003052
Make compound 6 (10 grams, 21.7 mmoles) from the preparation embodiment of WO02/18368A1 1 step D, press the same way as hydrolysis described in preparation embodiment 1 steps A of WO02/18368A1, and must title compound (11).MH+＝389.
Step B
Figure A0380472003061
In amine product that derives from preparation embodiment 2 steps A in being dissolved in anhydrous methylene chloride (100 milliliters) (20 grams, 0.5 mole) and the triethylamine (10.4 grams, 14.4 milliliters, 1.02 moles), add methylsulfonyl chloride (8.8 grams, 6 milliliters, 0.7 mole).After at room temperature stirring is spent the night, this solution is diluted with methylene dichloride, with saturated NaHCO 3Washing, and with anhydrous magnesium sulfate drying.Filter in a vacuum and concentrate, obtain crude product, make its on silicagel column by hurried formula chromatogram purification, with 1% CH 3OH (saturated)-CH with ammonia 2Cl 2Wash-out, and get title compound (12).MS(FAB)m/z469(MH +).
Step C
Will derive from the product (21.25 grams, 45.3 mmoles) of preparation embodiment 2 step B, press the same way as described in preparation embodiment 1 step e of WO42/18368A1 and handle, and 22.2 mixtures that digest compound (13) and (14).MS(473)(MH +).
Step D
Make to be dissolved among 150 milliliters of dense HCl, and stirred 16 hours from the product for preparing embodiment 2 step C (22.5 gram).Reaction mixture is poured in the ice, with dense NH 4The OH alkalization is then with CH 2Cl 2Extraction, the mixture of acquisition compound (15) and (16).MS(FAB)m/z405(MH +).
Preparation embodiment 2A
Steps A
Mat HPLC separates the compound of preparation embodiment 2 step B, uses the ChiralpackAD post, and with the 40-50% Virahol: 60-50% hexane-0.2% diethylamine wash-out obtains enantiomer amine (17) and (18).
Compound 17: fusing point=118-119; [α] 22 D=+136.9 ° (9.00 milligrams/2 milliliters, MeOH); MS (FAB) m/z469 (MH +).
Compound 18: fusing point=119-120; [α] 22 D=-178.2 ° (9.90 milligrams/2 milliliters, MeOH); MS (FAB) m/z469 (MH +).
Step B
Figure A0380472003101
Will derive from the product 17 (21.25 grams, 45.3 mmoles) of preparation embodiment 2A steps A, press the same way as described in preparation embodiment 1 step e of WO02/18368A1 and handle, and 22.2 mixtures that digest compound (31) and (32).MS(473)(MH +).
Preparation embodiment 4
Steps A
To the title compound (11) that derives from preparation embodiment 2 steps A (20 grams, 51.32 mmoles) at CH 3OH/H 2In the solution among the O (400 milliliters, 50: 1), add tert-Butyl dicarbonate (16.8 grams, 77.0 mmoles).The pH value is adjusted to 9, and mixture was stirred 4 hours.Remove and desolvate, add water then.With mixture with CH 2Cl 2Extraction.Make organic layer with dried over mgso, filter and be concentrated into dried, obtain title compound (23).MS491(MH +).
Step B
Figure A0380472003112
According to the similar approach for preparing embodiment 3 steps A as WO02/18368A1, preparation title compound (24).MS509(MH+).
Step C
In the solution of the title compound that derives from preparation embodiment 4 step B (19.62 grams, 38.5 mmoles) in ethanol (150 milliliters), add platinum oxide (IV) (1.962 gram).With reactant in H 2Stir under storage pressure gas-bearing formation and the room temperature and spend the night.Behind monitoring reaction, add other 2% (weight ratio) platinum oxide (IV), and at H 2Under the storage pressure gas-bearing formation, with reactant restir 6 hours.Make mixture through diatomite filtration and be concentrated into dried, and title compound (25), be white solid.MS511(MH +).
Step D
Make to be dissolved among the THF (30 milliliters), and in ice bath, be cooled to 0 ℃ from the product for preparing embodiment 4 step C (2.0 grams, 3.9 mmoles).In reactant, add diisobutylaluminium hydride (7.8 milliliters, 7.8 mmoles).Reactant is stirred and returns back to ambient temperature overnight.Reaction is not finished.In ice bath (0 ℃), make the mixture cooling, and add new diisobutylaluminium hydride/toluene (7.8 milliliters).After 4 hours, it is not still finished with the reactant restir.Make reaction mixture be cooled to 0 ℃, and add other 3.9 milliliters of diisobutylaluminium hydrides.With reactant restir 3 hours.Then, with crude reaction mixture with vinyl acetic monomer: 10% citric acid and 1.0NNaOH extraction.Make organic layer with dried over mgso, filter and be concentrated into dried, and desired title compound (26).MS471(MH +).
Step e
Figure A0380472003141
According to the similar approach described in the preparation embodiment 3 step C of WO02/18368A1, preparation title compound (27).MS549(MH +).
Step F
Figure A0380472003142
In the solution of the title compound that derives from preparation embodiment 4 step e (1.6 grams, 3.01 mmoles) in DMF (50 milliliters), add imidazolyl sodium (Aldrich) (0.407 gram, 4.52 mmoles).Reaction mixture was heated 2 hours at 90 ℃.Make the reactant cooling, and remove DMF.Add saturated sodium bicarbonate, and with mixture with CH 2Cl 2Extraction.Make organic layer with dried over mgso, filter and be concentrated into dried.Make crude product through the column chromatography purifying, with 2% CH 3OH: with the saturated CH of ammonia 2Cl 2Wash-out, and get title compound (28).MS519(MH +).
Step G
Make and be dissolved among 4N dioxane/HCl (20 milliliters) from the product for preparing embodiment 4 step F (0.55 gram, 1.08 mmoles).Reaction mixture was stirred under room temperature 3 hours, be concentrated into then dried, and title compound (29), be faint yellow solid.HRMS419(MH +).
Embodiment 506
Derive from the product (795.1) of WO02/18368A1 embodiment 489 step B:
Its diastereomeric separation is to reach by preparation HPLC, use preparation ChiralcelOD post, and with 20% IPA/ hexane+0.2% DEA (initial flow phase), with 25% IPA/ hexane+0.2% DEA (last moving phase) wash-out, obtain 795.1 isomer-1 (meaning is 795.1a) and 795.1 isomer-2 (meaning is 795.1b) then.
Isomer-1-MH+=536.1 (CDCL3,400MHz) 8.437 (d, 1H), 8.22 (d, 1H), 7.54 (s, 1H), 7.49 (d, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.19 (m, 1H), 7.10 (s, 1H), 6.57 (s, 1H), 4.57 (s, 1H), 3.86 (s, 3H), 3.21 (br, s, 4H), 2.24 (m, 2H), 1.98 (m, 2H), 1.90 (s, 3H), 1.41 (s, 9H) .m.p.195-197 ℃.
Isomer-2-MH+=536.1 (CDCL3,400MHz) 8.47 (d, 1H), 7.64 (d, and 1H) 7.64 (d, 1H), 7.54 (s, 1H), 7.5 (s, 1H), 7.35 (d, 1H), 7.23 (m, 1H), 7.21 (m, 1H), 7.22 (m, 1H), 7.14 (s, 1H), 6.8 (d, 1H), 4.59 (s, 1H), 3.76 (s, 3H), 3.23 (br.s.4H), 2.23 (m, 2H), 1.99 (m, 2H), 1.87 (s, 3H), 1.41 (s, 9H) .m.p.206-208 ℃.
Embodiment 507
Via at room temperature and N 2Make compound 795.1b (isomer 2,0.093 grams, 0.173 mmole) and CH down, 2Cl 2(5.0 milliliters)/TFA (1.0 milliliters) reaction makes it change into 795.2b.
Use same procedure, prepare 795.2a (isomer 1) from 795.1a.
Embodiment 508
Enantiomer 365a separates with 365b's, by chirality HPLC, uses the ChiralpakAD post, and reaches with IPA (20%) hexane (80%)+0.2% DEA wash-out.
Isomer 365a: retention time=7.65 minute; MH +=492.
Isomer 365b: retention time=12.16 minute; MH +=492, fusing point 95-100 ℃.
(, consulting WO02/18368A1) about compound 365.
Preparation embodiment 73
Steps A
Figure A0380472003182
(880) (2 equivalents, 14.2 mmoles) are dissolved among the THF (20 milliliters), add 1MliOH (16 milliliters), and at room temperature stirred 1 hour or till reaction is finished.Be evaporated to driedly,, obtain crude product (881), be solid then with toluene evaporates 3x.
Step B
Employing derives from the rough thing (881) of steps A, and is dissolved among the DMF (60 milliliters), and adds NH (OMe) Me (3.14 gram), DEC (6.14 gram), HOBT (2.16 gram), NMM (11 milliliters), and at room temperature stirs and spend the night.Add 1.0NHCl till being acid (pH=2), wash with ether.Add K 2CO 3, stir simultaneously, saturated with NaCl till alkalescence～pH=8, and with CH 2Cl 2Extraction (4x).With MgSO 4Drying is filtered and evaporation, obtains product (882) (3.23 gram).
Step C
Adopt rough thing (882) (14.2 mmole), and be dissolved among the THF (100 milliliters).In ice bath, cool off, and in 10 minutes, in N 2Dropwise add MeMgBr (3 volumetric molar concentrations are in ether) (22.2 milliliters) down.Make it be warmed to 40 ℃, and stirred 4 hours or till reaction is finished.In ice bath, cool off, and add saturated NH 4Cl.With ethyl acetate extraction, then with CH 2Cl 2Extraction 3x.With MgSO 4Drying is filtered and evaporation.Under vacuum, store, obtain crystal (883) 1.78 grams, 74%).
Step D
Figure A0380472003201
365 (0.24 gram, 0.49 mmoles) are dissolved among the THF (2.5 milliliters).In N 2Under be cooled to-78 ℃, add (1) (BuLi, 2.5M, 0.2 milliliter), and formed deep brown solution stirred 15 minutes.Feasible 883 (0.116 grams) from step C are dissolved among 0.5 milliliter of THF, and are added in the reactant, and stir 3 hours down at-78 ℃.Reaction mixture is added in the salt solution, and with ethyl acetate extraction (2x).With MgSO 4Drying is filtered and evaporation, obtains yellow solid.Make rough thing (0.29 gram) purifying by the preparation plate chromatography, and get the 0.0.15 gram, the product of (795.1) of 42% productive rate.
Embodiment 509
795.1???????????????????795.1
Isomer-1 isomer-2
(that is, 795.1a) (that is, 795.1b)
Press described in the embodiment 506,, use the ChiriralpakOD post, and use IPA (20%) hexane (80%)+0.2% DEA, compound 795.1 is separated into two kinds of diastereomers (isomer-1 and isomer-2) by chirality HPLC.
Embodiment 510
Steps A
Make 365a[0.9 gram, 1.83 mmoles] be dissolved among the anhydrous THF (15 milliliters), and be cooled to-75 ℃ (dry ice/acetone batch).Under-75 ℃, dropwise add (n-BuLi) [(2.5N is in hexane); 0.24 gram, 1.5 milliliters, 3.74 mmoles], and stir about 20 minutes.Add 5-formyl radical-1-Methylimidazole (0.3 gram, 2.75 mmoles are in 2 milliliters of THF) fast, and stirred 3 hours down in-75 ℃.With (H 2The O-vinyl acetic monomer) carries out TLC.Reaction is finished.Handle, its mode is to add 10 milliliters of H 2O, and with ethyl acetate extraction, and with the salt water washing, with MgSO 4Drying is filtered and evaporation, and is got crude product.Make rough thing through hurried formula chromatogram purification (silicagel column), use CH 2Cl 2/ 5% CH 3OH (15% NH 4OH), obtain 0.54 and digest compound 884,56% productive rates.
Step B
Figure A0380472003221
Make initial substance 884 (0.54 gram) be dissolved in CH 2Cl 2In, and add MnO 2(5 gram), and at room temperature stir and spend the night.At 75% CH 2Cl 2/ 25% EtOAc/5% MeOH (15% NH 4OH) carry out TLC in.Leach inorganic substance, and be evaporated to dried, and 0.49 the gram 885,90% productive rates.
Step C
Figure A0380472003222
Make 0.35 gram, 1.71 mmole (CH 3) 3S +I -Be dissolved among anhydrous DMSO (5 milliliters) and the THF (5 milliliters).Add sodium hydride (0.068 gram, 1.71 mmoles), stirred 10 minutes.Make mixture be cooled to 0 ℃.Add the initial substance 885 (0.3 gram, 0.577 mmole) in (DMSO-THF1:1,5 milliliters), and stirred 6 hours down, in refrigerating chamber, store 18 hours then in 0 ℃.With H 2O makes the stopping of reaction.With ethyl acetate extraction, and with the salt water washing, with MgSO 4Drying is filtered and evaporation, and is got 0.310 gram product 886.
Step D
886 (0.28 gram, 0.48 mmoles) are dissolved among the THF (5 milliliters), add Li (Et) 3BH (0.8 milliliter, 0.8 mmole).Stir after 1 hour, add～10 milliliters of 1NHCl to reactant, and stirred 5 minutes.Slowly add saturated sodium bicarbonate, up to alkalescence, and with ethyl acetate extraction (3X).Make organism with MgSO 4Drying is filtered and evaporation, and is got crude product.Column chromatography on 12 gram silica gel, and with 2% to 4% MeOHNH 4OH/CH 2Cl 2Wash-out obtains 170 milligrams, the pure products 887 of 66% productive rate.
Step e
Figure A0380472003241
Prepare HPLC by chirality, use the OD post of Chiral Technologies, and, separate 887, obtain compound with 20% isopropanol/hexane/0.2% DEA wash-out; 888a and 888b.
Embodiment 511-513
Make and be dissolved in CH from each isomer 795.2a and the 795.2b of embodiment 507 2Cl 2In, handle with corresponding isocyanate, and under room temperature, stir and spend the night.Make crude product through silica gel preparative thin layer chromatography method or silica gel chromatography direct purification, and get following formula: compound:
Wherein R is defined in the table 55, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 55
Embodiment 536
Make from each isomer 795.2a of embodiment 507 and 795.2b under room temperature and nitrogen, be dissolved in the dry DMF, then add corresponding carboxylic acid class and suitable reagent: EDC, HOBT and NMM.Then, reactant is stirred under room temperature spend the night.Except that desolvating, produce the oily residue via rotatory evaporator.Residue is dissolved in the methylene dichloride, and washs with 1.0NNaOH.With Na 2SO 4Drying is filtered and is concentrated.Make crude product by preparing the TLC purifying, use methylene chloride, obtain following formula: compound:
Wherein R is defined in the table 57, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 57
Embodiment 566-567
Make and be dissolved in anhydrous CH from each isomer 795.2a and the 795.2b of embodiment 507 2Cl 2In, then be dissolved in Et 3Among the N.Then, reactant is handled with its corresponding SULPHURYL CHLORIDE, and under room temperature, stirred and spend the night.Make the stopping of reaction with 1.0NNaOH, and with CH 2Cl 2Extraction.Make organic layer with MgSO 4Drying is filtered and is concentrated.Through the column chromatography purifying, with methyl alcohol-CH 2Cl 2Wash-out obtains following formula: compound:
Wherein R is defined in the table 59, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 59
Figure A0380472003271
* if according to described method, then will obtain the isomer 1 of embodiment 567.
Embodiment 590-603
Make and at room temperature be dissolved in the anhydrous methylene chloride from each isomer 795.2a and the 795.2b of embodiment 507.Make reactant be cooled to 0 ℃, and add TEA.Then, dropwise add chloro-formic ester separately, and reactant is stirred down in 0 ℃, till finishing.With 1.0NNaOH reactant is alkalized to pH=8-10, then with dichloromethane extraction.Merge organic layer, with MgSO 4Drying is filtered and is concentrated, and produces crude product.Through preparation TLC purifying, use methylene dichloride/acetone (95%/5%), obtain compound:
Wherein R is defined in the table 61, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 61
* if according to described method, then will obtain the isomer 1 of these embodiment.
Embodiment 592, the PMR data of isomer 1
(CD 3Cl)8.44(d，1H)，8.23(d，1H)，7.54(s，1H)，7.48(d，1H)，7.37(d，1H)，7.32(dd，1H)，7.18(dd，1H)，7.10(s，1H)，6.58(s，1H)，4.87(m，1H).4.58(s，1H).3.86(s，3H)，3.25(brs，4H)，2.26(brs，2H)，1.99(m，2H)，1.90(s，3H)，1.21(d，6H).
Preparation embodiment 74
Figure A0380472003301
(wherein R is alkyl (for example ethyl) or cycloalkyl (for example cyclohexyl))
Phosgene (3 milliliters, 1.93M is in toluene) is dissolved in the anhydrous diethyl ether, and is cooled to 0 ℃.Dropwise add cyclohexyl alcohol (200 milligrams, 2 mmoles) and the mixture of pyridine (0.18 milliliter, 2.2 mmoles) in ether (4 milliliters).After adding, make reactant be warmed to room temperature, stir simultaneously and spend the night.Then, with MgSO 4Be added in the reactant, and mixture was stirred 5 minutes.After filtration, make N 2Foaming enters in the solution, goes through 30 minutes.Then, make it be concentrated into 0.5 milliliter, with CH 3Ph (10 milliliters) dilutes, and is stored under 4 ℃ with stock solution.
Preparation embodiment 75
Steps A
Figure A0380472003302
With 15.4 gram (115 mmole) CuCl 2Be added into 400 milliliters of anhydrous CH with 17 milliliters of (144 mmole) nitrite tert-butyls 3Among the CN.Make reaction mixture be cooled to 0 ℃, and add 25 gram ketone (564).Make reactant be warmed to room temperature, and stirred two days.Mixture is concentrated under vacuum.Then, 1NHCl being added in the residue, is neutral up to the pH value, then adds NH 4OH is an alkalescence up to the pH value.Behind ethyl acetate extraction, make organic layer with MgSO 4Drying, and under vacuum, concentrate, and get compound 890.Perhaps, 889 correspondent alcohol can be by above-mentioned reaction, then with MnO 2At CH 2Cl 2Middle oxidation obtains compound 890.
Step B
Figure A0380472003311
To prepare the same way as of embodiment 23 steps A-D basically as WO02/18368, make from compound 890 reactions of above-mentioned steps A, obtain compound 891 and 892.
Step C
Press described in the embodiment 508, be separated into indivedual enantiomer 891a and 891b with 891, use chirality AD to prepare the HPLC post.
Step D
Figure A0380472003331
By described in 507 embodiment, the compounds 892 that the 6-bromine is replaced is separated into enantiomer 892a and 892b, uses chirality AD to prepare the HPLC post.
Preparation embodiment 76
Steps A
Use basically as the same procedure among the embodiment 510,891a and the product of preparation embodiment 73 are reacted, obtain 893.
Step B
Figure A0380472003341
Make 893 via chirality HPLC chromatogram, use the ChiralcelOD post, and, obtain 893a (meaning is an isomer 1) and 893b (meaning is an isomer 2) with IPA (20%) and hexane (80%) wash-out with 0.2%DEA.
Preparation embodiment 77
Steps A
Figure A0380472003342
Use basically as the same procedure among the embodiment 510,891b and the product of preparation embodiment 73 are reacted, obtain 893.
Step B
Figure A0380472003351
Make 894 via chirality HPLC chromatogram, use the ChiralcelOD post, and, obtain 894a (meaning is an isomer 1) and 894b (meaning is an isomer 2) with IPA (20%) and hexane (80%) wash-out with 0.2%DEA.
Preparation embodiment 78
Steps A
Figure A0380472003361
Use basically as the same procedure among the embodiment 510,892a and the product of preparation embodiment 73 are reacted, obtain 895.
Step B
Make compound 895 via chirality HPLC chromatogram, use the ChiralcelOD post, and, obtain 895a (meaning is an isomer 1) and 895b (meaning is an isomer 2) with IPA (20%) and hexane (80%) wash-out with 0.2%DEA.
Preparation embodiment 79
Steps A
Use basically as the same procedure among the embodiment 510,892b and the product of preparation embodiment 73 are reacted, obtain 896.
Step B
Figure A0380472003381
Make 896 via chirality HPLC chromatogram, use the ChiralcelOD post, and, obtain 896a (meaning is an isomer 1) and 896b (meaning is an isomer 2) with IPA (20%) and hexane (80%) wash-out with 0.2%DEA.
Preparation embodiment 80
Make compound 893a and 893b change into 897a and 897b, its mode is at room temperature and N 2Make itself and CH down, 2Cl 2/ TFA reaction 2 hours.Under vacuum, concentrate.Make residue be dissolved in CH 2Cl 2In, and wash with 1.0NaOH.With MgSO 4Drying is filtered and is concentrated, and obtains 897a (meaning is an isomer 1) and 897b (meaning is an isomer 2).
Preparation embodiment 81
Figure A0380472003401
According to basically as the same procedure of preparation among the embodiment 80, in room temperature and N 2Make compound 894a and 894b respectively and TFA/CH down, 2Cl 2Reacted 2 hours, and obtained compound 898a (meaning is an isomer 1) and 898b (meaning is an isomer 2).
Preparation embodiment 82
Use basically as the same procedure among the preparation embodiment 80, in room temperature and N 2Make 895a and 895b respectively and TFA/CH down, 2Cl 2Reacted 2 hours, and obtained compound: 899a (meaning is an isomer 1) and 899b (meaning is isomer 899b).
Preparation embodiment 83
Figure A0380472003421
Use basically as the same procedure among the preparation embodiment 80, in room temperature and N 2Make 896a and 896b respectively and TFA/CH down, 2Cl 2Reacted 2 hours, and obtained compound: 900a (meaning is an isomer 1) and 900b (meaning is an isomer 2).
Preparation embodiment 84
With initial substance 901 (25 grams, 78 mmoles) and DBU (15.7 milliliters, 105.3 mmoles, 1.35 equivalents); Ph 3P (9.44 grams, 0.39 mmole, 0.5 equivalent); PdCl 2(1.38 grams, 7.8 Bo moles, 0.1 equivalent); MeOH (50 milliliters)/toluene (200 milliliters) merges in flask, and in Parr shaker, in CO100psi and 80 ℃ of reactions down.When finishing, with reactant with H 2O handles, and with ethyl acetate extraction.With MgSO 4Dry also evaporation obtains the black slurries.(71 gram) column chromatography (silica gel), and with hexane, then with 20% vinyl acetic monomer/hexane to the 40%E/H wash-out, and product 902 (39 gram).
Preparation embodiment 85
Figure A0380472003431
Make (Bu) 4NNO 3(21.15 gram) is dissolved in CH 2Cl 2In (220 milliliters), and in ice bath, in N 2Following cooling, and drip TFAA (9.8 milliliters), and stirred 15 minutes.Formed yellow solution slowly is added into initial substance 902 (18.97 gram) at CH 2Cl 2In the solution in (200 milliliters), cooling (0 ℃) in ice bath simultaneously.Stirred 15-20 minute down in 0 ℃, make it be warmed to room temperature then, went through 3 hours.With reactant with saturated NaHCO 3Handle, and with CH 2Cl 2Extraction.Separate organic layer, and with MgSO 4Drying is evaporated to driedly, obtains product, is slurries.Make rough thing in SiO 2Last chromatogram (twice) is used hexane, then with 20% and 40% vinyl acetic monomer/hexane wash-out.The product 903 of 30-40% productive rate (7.89 gram).
Preparation embodiment 86
With Ra-Ni ((50%, in H 2Among the O), 50 grams) with ETOH washing (5X analyses then),, then be added in the initial substance 903 (7.89 gram) among the MeOH (80 milliliters) with MeOH washing (3X), with formed mixture in H 2(gas cylinder) stirs down and spends the night.By TLC monitoring reaction.Add other RaNi (25 grams are with ETOH washing 5X, then with MeOH3X).When finishing, the filtering reaction thing, with insoluble dark-coloured solid with CH 2Cl 2/ MeOH washing, till the washing lotion look thin out, merging filtrate, and be evaporated to driedly, obtain brown solid 904 (3.88 gram product).
Preparation embodiment 87
Figure A0380472003442
Make initial substance 904 (0.5 gram) be suspended in CH 3Among the CN (20 milliliters), add CuBr (0.42 gram), and in ice bath, at N 2Following cooling.Add t-BuONO (0.28 gram), and with its stirring and be warmed to room temperature.After stirring 2 hours under 75 ℃, stir about 2 hours.After reaction is finished, add reactant and to 1NHCl, also stir.Then, add dense NH 4OH is till blue (alkalescence).With CH 2Cl 2Extraction separates organic layer, with MgSO 4Drying is filtered and is concentrated, and gets product 905.
Preparation embodiment 88
Figure A0380472003451
With initial substance 905 (3 gram, 7.92 mmoles) in MeOH (100 milliliters), under 0 ℃, at ice/H 2O stirs in bathing, then with NaBH 4Portion-wise addition is to cold soln.Stirred 1 hour then at room temperature 1 hour down in 0 ℃.Add (20 milliliters) 1.0NHCl, stirred 10 minutes, with saturated NaHCO 3Alkalization is added in the salt solution, with ethyl acetate extraction, with MgSO 4Drying, filter and be evaporated to dried, and 3.6 digest compound 906.
Preparation embodiment 89
With SOCl 2(2.1 milliliters) are added into 906 (3.5 grams) at CH 2Cl 2In the solution in (50 milliliters), under room temperature, stirred 5 hours.Add (1.0 milliliters) SOCl in addition 2, stirred 2 hours, spend the night then.By TLC monitoring reaction progress.It is dried that reaction mixture is evaporated to, and dry under vacuum, obtains 3.6 gram crude products 907.
Preparation embodiment 90
Boc-piperazine (2.2 gram, 2.5 equivalents) is added into initial substance 907 (1.78 grams, 4.68 mmoles) and TEA (1.9 milliliters, 3 equivalents) at CH 3In the middle stirred mixture of CN (100 milliliters), in N 2Under be heated to 80 ℃, heated 5 hours.TLC stirs down at 80 ℃ then and spends weekend.Reactant is handled with 1.0NHCl, and with ethyl acetate extraction, with salt solution, then with the 1.0NNaOH washing, with MgSO 4Dry.Filter, and it is dried that reactant is evaporated to, and get rough 908 (62% productive rates).
Preparation embodiment 91
Figure A0380472003462
12 milliliters of 10%LiOH solution (about 4M) are added in the solution of initial substance 908 (1.6 gram) in MeOH (50 milliliters), and reactant is stirred down in 60 ℃.Solid precipitation is separated out.The mixture stirring is spent the night.Reactant becomes glassy yellow solution.With reactant with 10%K 2HPO 4Handle, and with ethyl acetate extraction, with the salt water washing, with MgSO 4Drying, and be evaporated to driedly, obtain 1.5 and digest compound 909.
Preparation embodiment 92
With initial substance 909 (1.5 grams ,-7.8 mmoles); NHCH 3OCH 3HCl; NMM; HOBT; ﹠amp; DMAP is at CH 2Cl 2Merge in (20 milliliters), and stirred 10 minutes, add EDC (0.64 gram, 1.2 equivalents) then, and at room temperature stir and spend the night.Reactant is handled with 1NHCl,,, then washed with 1NNaOH with salt solution with ethyl acetate extraction.With MgSO 4Drying is filtered, and evaporated filtrate is extremely dried, and gets (1.45 gram) crude compound 910.
Preparation embodiment 93
With CH 3The 3M solution of MgBr/ ether (3.8 milliliters, 4.5 equivalents) dropwise is added in 910 (1.45 grams, 2.5 mmoles) solution in THF (50 milliliters), causes deep brown solution.With reactant in N 2And stirred 2 hours under the room temperature.Then, with reactant with saturated NH 4The Cl solution-treated, and with ethyl acetate extraction.With the salt water washing, and with MgSO 4Drying filters and is evaporated to dried, obtains the yellow solid compound, and it obtains 1.33 and digest compound 911 after column chromatography, is racemic mixture.
Preparation embodiment 94
Figure A0380472003481
Make initial substance 911 (0.90 gram) be dissolved in CH 2Cl 2Among (35 milliliters) and the TFA (35 milliliters), and at room temperature stir and spend the night.With the 1.0NNaOH washing, with MgSO 4Drying, filter and be evaporated to dried, and compound 912.
Preparation embodiment 95
Prepare HPLC by chirality, use chirality AD post, and, be separated into its enantiomer, acquisition compound 912a and 912b 912 with 10%IPA/90% hexane+0.2%DEA wash-out.
Preparation embodiment 96
Figure A0380472003501
Make initial substance 912a (0.284 gram, 0.656 mmole) be dissolved in CH 2Cl 2(5 milliliters), TEA (1.83 milliliters, 2.0 equivalents) reach (BOC) 2Among the O (0.215 gram, 1.5 equivalents), and at room temperature stir and spend the night.Make the reactant evaporation, and make rough thing, use 10%﹠amp through the column chromatography purifying; 25 vinyl acetic monomers/hexane digest compound 913a and get 0.3.
Preparation embodiment 97
Make initial substance 9121b (0.254 gram, 0.587 Bo mole) be dissolved in CH 2Cl 2(5 milliliters), TEA (1.64 milliliters, 2.0 equivalents) reach (BOC) 2Among the O (0.192 gram, 1.5 equivalents), and at room temperature stir and spend the night.Make the reactant evaporation, and make rough thing, use 10%﹠amp through the column chromatography purifying; 25 vinyl acetic monomers/hexane obtain 0.255 and digest compound 913b.
Preparation embodiment 98
Steps A
Figure A0380472003511
915 (30 grams, 68.8 mmoles) that make commercial getting (deriving from Acros) are at dry N 2Be suspended among the anhydrous THF (600 milliliters) down.In room temperature and N 2Following stirring is till it forms clear solution.At room temperature and dry N 2Dropwise add CH down, 3I (50 milliliters, 114 grams, 803.2 mmoles).With this suspension in room temperature and N 2Under stirred 4 days, then be TLC-(10%MeOH-2MNH 3/ CH 2Cl 2).With this suspension filtered, with anhydrous THF washing solid.Make solid under the vacuum of chamber, dry under 40 ℃, and get 31.11 gram brown solid compounds 916.
Step B
Figure A0380472003512
Make 916 (31.1 grams, 53.79 mmoles) be suspended in 200 milliliters of 50%HOAC/H 2Among the O, and under refluxing heated overnight.Then be TLC.When finishing, make it be cooled to room temperature, filter formed suspension.With 50%HOAC/H 2The O washing.Be evaporated to dried.Make solid suspension in CH 2Cl 2In.Alkalize to pH10-11 with 1NNaOH.Separation of C H 2Cl 2The layer, and with water with CH 2Cl 2Extraction 3x.Merge organic layer, and with saturated NaCl solution washing.With MgSO 4Drying is evaporated to driedly, obtains 914 (8.68 gram pale solids).
Preparation embodiment 99
Steps A
(3 volumetric molar concentrations are in Et with EtMgBr 2Among the O) solution (2.89 mmoles, 963 microlitres, 5.5 equivalents) splash into 914 (0.656 gram, 3.15 mmoles, 6 equivalents) at ClCH 2CH 2In the solution among the Cl (6 milliliters), went through 30 minutes.In this white suspension mixture, then add 913a (0.280 gram, 0.525 mmole), and stirred 3 hours down at 60 ℃.Under 0 ℃, with reactant with saturated NH 4Cl handles, and its mode is to cold NH with reactant 4Among the Cl.With ethyl acetate extraction, with MgSO 4Drying, and be evaporated to dried.Column chromatography (SiO 2), with 1%, 2% and 3%MEOH/CH 2Cl 2Wash-out obtains 0.054 and digests compound 917.
Step B
Figure A0380472003531
By HPLC, use chirality OD post, and,, and get 917a (isomer 1) and 917b (isomer 2) 917 separation with 20%IPA/ hexane wash-out.
Preparation embodiment 100
Figure A0380472003541
(3 volumetric molar concentrations are in Et with EtMgBr 2Among the O) solution (791 microlitre) splash into 914 (0.518 gram, 3.15 mmoles, 6 equivalents) at ClCH 2CH 2In the solution among the Cl (6 milliliters), went through 30 minutes.In this white suspension mixture, then add 913b (0.280 gram, 0.525 mmole), and stirred 3 hours down at 60 ℃.Under 0 ℃, with reactant with saturated NH 4Cl handles, and its mode is to cold NH with reactant 4Among the Cl.With ethyl acetate extraction, with MgSO 4Drying, and be evaporated to dried.Column chromatography (SiO 2), with 1%, 2% and 3%MEOH/CH 2Cl 2Wash-out obtains 0.054 and digests compound 918.
Step B
Figure A0380472003551
By HPLC, use chirality OD post, and,, and get isomer 918a 918 separation with 20%IPA/ hexane wash-out
1H NMR (400MHz, CDCl 3, TMS) 61.419 (s, 9H), 1.457 (s, 1H), 1.894 (s, 3H), 2.05-1.87 (m, 2H), 2.30-2.15 (m, 2H), 3.214 (wide, 1H), 3.540 (s, 1H), 3.738 (s, 1H), 3.760 (s, 1H), 3.888 (s, 3H), 4.540 (s, 1H), 6.479 (s, 1H), 7.128 (s, 1H), 7.260 (d, 1H), 7.340 (s, 2H), 7.627 (d, J=2.4Hz, 1H), 8.221 (s, 1H), 8.486 (d, J=2.8Hz, 1H), (21) Mp=188-190 ℃, and 918b.
Preparation embodiment 101
At room temperature and N 2Down, via with CH 2Cl 2/ TFA reaction 2 hours makes compound 917a change into 919a.Then, reactant is concentrated, and make residue be dissolved in CH 2Cl 2In, and wash with 1.0NaOH.Make isolating organic substance with MgSO 4Drying is filtered and is concentrated, and gets compound 919a.
Preparation embodiment 102
Figure A0380472003562
At room temperature and N 2Down, via with CH 2Cl 2/ TFA reaction 2 hours makes Compound C armen917b change into 919b.Then, reactant is concentrated, and make residue be dissolved in CH 2Cl 2In, and wash with 1.0NaOH.Make isolating organic substance with MgSO 4Drying is filtered and is concentrated, and gets compound 919b.
Preparation embodiment 103
Figure A0380472003571
At room temperature and N 2Down, via with CH 2Cl 2/ TFA reaction 2 hours makes compound 918a change into 920a.Then, reactant is concentrated, and make residue be dissolved in CH 2Cl 2In, and wash with 1.0NaOH.Make isolating organic substance with MgSO 4Drying is filtered and is concentrated, and gets compound 920a.
Preparation embodiment 104
At room temperature and N 2Down, via with CH 2Cl 2/ TFA reaction 2 hours makes compound 918b change into 920b.Then, reactant is concentrated, and make residue be dissolved in CH 2Cl 2In, and wash with 1.0NaOH.Make isolating organic substance with MgSO 4Drying is filtered and is concentrated, and gets compound 920b.
Preparation embodiment 105
Steps A
To prepare same way as among embodiment 23 steps A-D as WO02/18368 basically, make compound 921 reactions, obtain compound 922.
Step B
To prepare same way as in embodiment 42 steps A as WO02/18368 basically, use 922 as initial substance, make compound 923.
Preparation embodiment 106
Figure A0380472003591
, make as the same way as among the preparation embodiment 91-104 with basically from compound 923 reactions that prepare embodiment 105 step B, acquisition 924a (meaning is an isomer 1) and 924b (meaning is an isomer 2).
Preparation embodiment 107
, make as the same way as among the preparation embodiment 91-104 with basically from compound 923 reactions that prepare embodiment 105 step B, acquisition 925a (meaning is an isomer 1) and 925b (meaning is an isomer 2).
Embodiment 1295
As the same procedure (wherein chloro-formic ester is to make according to the method for preparing among the embodiment 74) of embodiment 590-603, use following formula 924a and 924b compound according to basically:
Be prepared, wherein R is defined in the table 91, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 91
Figure A0380472003612
Embodiment 1314
As the same procedure (wherein chloro-formic ester is to make according to the method for preparing among the embodiment 74) of embodiment 590-603, use following formula 924a and 924b compound according to basically:
Be prepared, wherein R is defined in the table 93, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 93
Figure A0380472003622
Preparation embodiment 108
Steps A
To prepare the same way as of embodiment 23 steps A-D basically as WO02/18368, use compound 234a (deriving from step B) preparation 926.
Step B
Figure A0380472003632
To prepare the same way as of embodiment 42 steps A basically as WO02/18368, use 926 preparations 927.
Step C
, make as the same way as among the preparation embodiment 91-104 with basically, obtain compound 928a and 928b from compound 927 reactions of step B.
Step D
Figure A0380472003642
, make as the same way as among the preparation embodiment 91-104 with basically, obtain compound 929a and 929b from compound 927 reactions of step B.
Embodiment 1573
Steps A
According to preparing the method described in the embodiment 73 step C, make from 882 and the ethyl-magnesium-bromide reaction for preparing embodiment 73 step B.
Step B
, make 365a and 931 (deriving from steps A) reaction, and get 930 as the same procedure among the preparation embodiment 73 step D according to basically, be white solid, fusing point=163-165 ℃.
Embodiment 1574
Steps A
Make 880 (1.4 grams, 10 moles), CF 3TMS (1.46 grams, 10.25 moles) and CsF (15.2 milligrams, 0.1 mmole) are dissolved among 15 milliliters of THF.At room temperature stir and spend the night, under vacuum, concentrate then.Make residue hurried formula chromatogram on silica gel, use the 0.5%-1% methyl alcohol in the methylene dichloride, obtain 933.
Step B
Figure A0380472003671
, make 365a and 933 (deriving from steps A) reaction, and get 932, fusing point=189.9-190.1 ℃ as the same procedure among the preparation embodiment 73 step D according to basically.
Embodiment 1575
372 (embodiment 167 of WO02/18368) (0.06 gram, 0.097 mmole) and 5 equivalents (0.019 gram, 0.48 mmole) NaH (60%, in oil) were reacted 5 minutes down in 0 ℃ in 2 milliliters of anhydrous THF.Add 0.027 gram (0.11 mmole) 4-(brooethyl) pyridine.Promote temperature to 60-65 ℃, and continue to add NaH and 4-(brooethyl) pyridine, up to through TLC (at CH 2Cl 2In 5%CH 3OH contains NH 4OH) till principal reaction finishes.Making separatory between vinyl acetic monomer and salt solution handles.With Na 2SO 4Make the organic layer drying, concentrate, and on silica gel chromatogram, to contain NH 4The CH of OH 2Cl 2In 1%-4%CH 3The OH wash-out obtains 934, is faint yellow solid.
Embodiment 1576
As the same procedure among the embodiment 1575, make compound 372 and 2-(brooethyl) pyridine HBr reaction according to basically, and the compound 935 that must in following table 105, confirm.
Embodiment 1577
As the same procedure among the embodiment 1575, make compound 372 and 3-(brooethyl) pyridine HBr reaction according to basically, and the compound 936 that must in following table 105, confirm.
Embodiment 1578
As the same procedure among the embodiment 1575, make compound 372 and cylite reaction according to basically, and the compound 937 that must in following table 105, confirm.
Embodiment 1579
As the same procedure among the embodiment 1575, make compound 372 and CH according to basically 3I reaction, and the compound 938 that must in following table 105, confirm.
Table 105
Figure A0380472003681
Embodiment 1580
Figure A0380472003692
Steps A
In 125 ml flasks, add 4-hydroxymethyl piperidine (940) (1 gram, 8.68 mmoles) and 20 milliliters of MeOH, be cooled to 0 ℃, add Boc-acid anhydrides (2.84 grams then, 13.02 mmole, 1.5 equivalents), and in 1 hour, with 13 milliliters, 13.0 mmole, 1.5 equivalent 1.0NNaOH are adjusted to pH8.5-9.5.Make reactant be warmed to room temperature, and stirred 1 hour.TLC uses 20%EtOAc/CH 2Cl 2Remove most MeOH via evaporation.Add CH 2Cl 2, and with H 2O, salt water washing, and through Na 2SO 4Filter.Evaporating solvent obtains 1.82 gram clean oils.When leaving standstill, make the crystallization of oily product, and get white solid product 941.
Step B
941 (0.3 gram, 1.395 mmoles) are transferred in the flask, and are dissolved in anhydrous CH 2Cl 2In.Be cooled to 0 ℃.Add 129 microlitres, 1.67 mmoles, 1.2 equivalent methylsulfonyl chlorides and triethylamine (129 microlitres, 2.09 mmoles, 1.5 equivalents).Make it be warmed to room temperature, stirred simultaneously 1 hour.TLC uses 20%EtOAc/CH 2Cl 2Add saturated NaHCO 3, and stirred separation of C H 3-4 minute 2Cl 2Layer is with H 2O, salt water washing, and through Na 2SO 4Filter.Evaporating solvent obtains 0.423 gram clean oil, compound 942.
Step C
Figure A0380472003711
942 (0.1 gram, 3.413 mmoles) are transferred in the reaction flask, and add anhydrous CH 2Cl 2(1 milliliter) then adds (1) 4-anthranilo nitrile (0.040 gram, 3.4 mmoles) and triethylamine (61 microlitres, 4.4 mmoles, 1.3 equivalents), and at room temperature stirred 10 minutes.TLC uses 10%EtOAc/CH 2Cl 2, get principal reaction and remain unfulfilled.Stirred 11/2 hour, again-inferior TLC, stopped reaction.Remove and desolvate to doing.Under room temperature, (1 milliliter) anhydrous THF is added in the residue, add 0.0136 gram then, 3.4 mmole NaH (60%, in oily dispersion liquid).Make it stir 1/2 hour, then make progress through the TLC assaying reaction.Other NaH (0.0136 gram, 3.4 mmoles) is added in the reaction mixture, stirred 1/2 hour, mat TLC monitors reaction, in oil bath, reaction mixture is heated to 60 ℃ then, goes through 45 minutes, then spends the night.Under vacuum, in rotatory evaporator, remove and desolvate.Make residue be dissolved in CH 2Cl 2In, and with H 2O is then with the salt water washing.Through Na 2SO 4Filter, remove and desolvate, restrain crude product and get 0.125 to doing.Make rough thing through hurried formula chromatogram purification, use in (silica gel), and with CH 2Cl 2, then with 1-5%EtOAc/CH 2Cl 2Wash-out.Separate 0.035 gram product, 943.
Step D
Figure A0380472003721
943 (0.034 gram, 0.11 mmoles) are transferred in the reaction flask, and are dissolved in CH 2Cl 2In (3 milliliters), and be cooled to 0 ℃.Adding TEA (60 microlitres, 0.43 mmole, 4 equivalents), then is (213 microlitres, 0.0427 gram, 0.43 mmole, 4 equivalents) 20% phosgene/toluene solution.Reactant was stirred 11/2 hour down at 0 ℃.After 11/2 hour, make N 2Foaming enters in the reactant, goes through about 10 minutes, adds 0.056 gram then, 0.12 mmole, and 1.1 equivalent initial substance (2)-compound 371a (WO02/18368 prepares embodiment 42 step F) then are 1 milliliter of CH 2Cl 2In triethylamine (33 microlitres, 0.24 mmole, 2.2 equivalents).It was stirred 11/2 hour down at 0 ℃.With reaction mixture with NaHCO 3, then with H 2O then with the salt water washing, and makes organic layer through Na 2SO 4Filter.Remove and desolvate, obtain 0.083 gram crude product to doing.Purifying on hurried formula silicagel column is with 2,4,6,8% (10%NH 4OH/CH 3OH)/CH 2Cl 2Wash-out.Separated product obtains 0.039 gram 939, MH +=747.
Embodiment 1581
With as the compound 360a same way as of (WO02/02/18368 prepares embodiment 40 step G), use (0.118 gram, 0.25 mmole) 939 and (5 milliliters) 4NHCl in dioxane, make 939 reactions, and get 0.252 gram 944, MH +=647.
Embodiment 1582
In 100 ml flasks, add 944 (0.073 gram, 0.067024 mmoles) and 5 milliliters of anhydrous CH 2Cl 2And stir, then add TEA (37 microlitres, 4 equivalents) and isocyanic acid trimethyl silyl ester (90 microlitres, 0.07 mmole, 10 equivalents).Reactant was stirred under room temperature 1 hour.TLC uses 7% (10%NH 4OH/CH 3OH)/CH 2Cl 2Stirred 11/2 hour, and added saturated NaHCO then 3, and stirred separation of C H 10 minutes 2Cl 2Layer, and with H 2O, salt water washing, and with Na 2SO 4Drying is filtered, and concentrated filtrate obtains 0.056 gram crude product to doing.Purifying on hurried formula silicagel column is with CH 2Cl 2, then with 1-7% (10%NH 4OH/CH 3OH)/CH 2Cl 2Wash-out.Separate the desired product 945 of 0.038 gram, MH +=690.
Embodiment 1583
Figure A0380472003741
In 50 milliliters of reaction flasks, add 1 milliliter of dry DMF and 1 milliliter of anhydrous CH 2Cl 2In (0.0092 gram, 0.0882 mmole, 1.05 equivalents) 2-hydroxy-iso-butyric acid [CAS594-61-6], then add NMM (46 microlitres, 0.42 mmole, 5 equivalents); HOBT (0.0178 gram, 0.11 mmole, 1.3 equivalents), DEC (0.024 gram, 0.13 mmole, 1.5 equivalents).With reaction mixture stir about 10 minutes at room temperature, add 1 milliliter of DMF and 1 milliliter of CH then 2Cl 2In 944 (0.084 gram, 0.08 mmole, 1 equivalents).Reactant stirred under room temperature spend the night.In rotatory evaporator, remove and desolvate, add EtOAc, and with saturated NaHCO 3, then with H 2O3 (X) is then with the salt water washing.Make organic layer through Na 2SO 4Filter, evaporated filtrate obtains 0.087 gram crude product to doing.Make rough thing purifying on hurried formula silicagel column, with CH 2Cl 2-1-5% (10%NH 4OH/CH 3OH)/CH 2Cl 2Wash-out, and get 0.048 gram white solid compound 946, MH +=733.
Embodiment 1584
Will (0.084 gram, 0.084 mmole) 944 and 2 milliliters of anhydrous CH 2Cl 2Be transferred in 50 ml flasks, then add triethylamine (50 microlitres, 4.2 mmoles, 5 equivalents) and methylsulfonyl chloride (7.8 microlitres, 0.10 mmole, 1.2 equivalents).Reactant stirred under room temperature spend the night.TLC uses 5% (10%NH 4OH/CH 3OH)/CH 2Cl 2Add saturated NaHCO 3, and high degree of agitation 5-10 minute.Separation of C H 2Cl 2Layer, and with H 2O, salt water washing, and through Na 2SO 4Filter.Evaporated filtrate obtains 0.080 gram crude product to doing.Make rough thing purifying on hurried formula silicagel column, with CH 2Cl 2-1-4% (10%NH 4OH/CH 3OH)/CH 2Cl 2Wash-out, and get 0.041 gram-compound 947, MH +=725.
Embodiment 1585
Will (0.084 gram, 0.084 mmole) 944 and 2 milliliters of anhydrous CH 2Cl 2Be transferred in 50 ml flasks, then add triethylamine (58 microlitres, 4.2 mmoles, 5 equivalents) and trifluoromethanesulfanhydride anhydride (16.9 microlitres, 0.1008 mmole, 1.2 equivalents).Reactant stirred under room temperature spend the night.TLC uses 5% (10%NH 4OH/CH 3OH)/CH 2Cl 2Add saturated NaHCO 3, and high degree of agitation 5-10 minute.Separation of C H 2Cl 2Layer, and with H 2O, salt water washing, and through Na 2SO 4Filter.Evaporated filtrate obtains 0.065 gram crude product to doing.Make rough thing purifying on hurried formula silicagel column, with CH 2Cl 2-1-4% (10%NH 4OH/CH 3OH)/CH 2Cl 2Wash-out, and get 0.028 gram-compound 948, MH +=779.
Embodiment 1586
Steps A
Figure A0380472003772
Make 4-anthranilo nitrile (0.1 gram, 0.85 mmole) be dissolved in (5 milliliters) CH 2Cl 2In.In this solution, add (1, the 1-dimethyl ethylene oxide) epoxy Trimethylmethane (61 milligrams, 0.85 mmole) and 1 gram silica gel.Reaction mixture was at room temperature stirred 16 hours.Add epoxy Trimethylmethane (0.75 microlitre, 8 mmoles), and reactant is heated to 60 ℃, heated 16 hours.Add 4-anthranilo nitrile (200 milligrams, 1.6 mmoles) and 1,1-dimethyl ethylene oxide (0.75 microlitre, 8 mmoles), and reactant was refluxed 7 hours again.The evaporating volatile solvent, and make this material chromatogram on silicagel column, with 1-9% vinyl acetic monomer/CH 2Cl 2Wash-out obtains 295 milligrams of desired products-951.
Step B
To derive from the compound 951 of steps A, use standard conditions, carry out N-protected, and get 952 with the Boc group.
Step C
To derive from the compound 952 of step B, use tetrabutyl dimetylsilyl (TBDMS) to carry out the O-protection, obtain 953.
Step D
Figure A0380472003783
With the Boc group of 953 step C, use the HCl-dioxane to remove protection, and get 954.
Step e
To derive from the compound 954 of step D, handle, obtain 955 in the mode of similar embodiment 1580 step D compounds.
Step F
Figure A0380472003792
Via handling, make and remove protection, and get title compound 949 from the compound 955 of step e with tetrabutylammonium (TBAF).
Embodiment 1587
Figure A0380472003801
956 and 957 is the similar fashion with 949, uses the initial epoxide that suitably replaces to make.
Preparation embodiment 109
Steps A
Figure A0380472003802
To 1,2 dimethylimidazole, compound 958 (1.92 grams, 1 equivalent, 20 mmoles) at 50 milliliters of Et 2Among the O in stirred solution, add BuLi (2.5M, in hexane, 1 equivalent, 20 mmoles, 8 milliliters), and under room temperature, stir, cause yellow suspension.Stirred 1.5 hours, and formed more throw outs.Reaction mixture is handled with 3.5 milliliters of DMF, stirred 2-5 hour, or till reaction is finished.With NH 4Cl solution makes the stopping of reaction, and with CH 2Cl 2The extraction, with organism with salt water washing 3x.Separation of organic substances, and be evaporated to driedly, obtain product, be rough thing.Self-control slave board chromatography is with 10: 1CH 2Cl 2: MeOH: 2NNH 3Purifying obtains 0.52 and digests compound 959, about 21%.
Step B
Figure A0380472003811
As the same procedure of embodiment 510 (steps A), but use compound 959 (0.25 gram, 2 mmoles) according to basically, preparation compound 960 as intermediate.Yellow solid (0.54 gram), 50% productive rate.
Step C
Figure A0380472003812
As the same procedure of embodiment 510 (step B), but use compound 960 (0.45 gram, 0.84 mmole) according to basically, preparation compound 961 as initial substance.Faint yellow solid (0.372).
Step D
As the same procedure of embodiment 510 (step C), but use compound 961 (0.267 gram, 0.5 mmole) according to basically, preparation compound 962 as initial substance.
Step e
As the same procedure of embodiment 510 (step D), but use compound 962 (0.5 mmole) according to basically, preparation compound 963 (0.18 gram) as initial substance.
Step F
, through chirality HPLC compound 963 is separated, and get compound 963a and 963b as the same procedure of embodiment 510 (step e) according to basically.Chirality OD prepares the HPLC post, with IPA (10%) hexane (80%)+0.2%DEA wash-out
Isomer 1, compound 963a: retention time=7.61 minute
Isomer 2, compound 963b: retention time=10.56 minute
Preparation embodiment 110
Steps A
In 964 (4-methyl-5-imidazole-ethyl formate, 7.7 grams, 50 mmoles) stirred solution in 100 milliliters of acetone, at room temperature, portion-wise addition K 2CO 3(6.9 grams, 50 mmoles).Under room temperature, stirred 25 minutes, add MeI (5 milliliters, 80 mmoles), stir 2.5 hours (through TLC monitoring reaction).Add other K 2CO 3(3.09 grams, 22 mmoles) and MeI (3 milliliters).Reactant was stirred 16 hours, filter reaction mixture then, and wash with acetone (80 milliliters).Obtain transparent filtrate.Evaporated filtrate, and make residue chromatogram (eluent methylene chloride (60: 1)), and get 1.8 gram solids.Make this solid mat through preparation plate chromatography ((20: 1) CH 2Cl 2: MeOHNH 3) purifying, compound is still impure.Carry out another time column chromatography ((50: 1) CH 2Cl 2: MeOHNH 3), and get 383 milligrams of desired product compounds 965.
Step B
To compound 965 (680 milligrams) in 10 milliliters of THF in stirred solution, under-78 ℃, dropwise add the 1.0MLAH (5.0 milliliters) among the THF.Reaction stirred, and make it be warmed to ambient temperature overnight.Make reaction mixture be cooled to 0 ℃, dropwise add 5 milliliters of H then 2O.Make reactant be warmed to room temperature, stirred simultaneously 1 hour.Through diatomite filtration, and with 20 milliliters of THF/40 milliliter H 2The O flushing.Obtain transparent filtrate.Filter, compound 966 is provided.
Step C
To compound 966 (about 4 mmoles) in stirred solution, at room temperature, add (3.0 gram) MnO 2, cause suspension.Reaction mixture is heated to gentle reflux, kept 18 hours.Add other MnO 2/ THF (/ 20 milliliters of 6.0 grams).Stirred 24 hours down in refluxing.Be cooled to room temperature, through diatomite filtration, and with 50 milliliters of MeOH flushings.Evaporating solvent, and make residue and methylbenzene azeotropic, and get crude product.Make rough thing through column chromatography purifying (20: 1CH 2Cl 2/ MeOH), be (8: 1CH then 2Cl 2: MeOH), wash-out goes out desired product, is white solid, compound 967.
Step D
If as the same procedure of embodiment 510 (steps A), but use compound 967 according to basically, then can prepare compound 968 as intermediate.
Step e
If as the same procedure of embodiment 510 (step B), but use compound 968 according to basically, then can prepare compound 969 as initial substance.
Step F
If as the same procedure of embodiment 510 (step C), but use compound 969 according to basically, then can prepare compound 970 as initial substance.
Step G
If as the same procedure of embodiment 510 (step D), but use compound 970 according to basically, then can prepare compound 971 as initial substance.
Step H
Figure A0380472003871
If as the same procedure of embodiment 510 (step e), then compound 971 can separate by chirality HPLC, and gets compound 971a and 971b according to basically.
Preparation embodiment 111
Steps A
Figure A0380472003872
To 972 (4-methyl-5-imidazole-ethyl formate, 3.08 grams, 20 mmoles) in 30 milliliters of THF in stirred solution, under room temperature, portion-wise addition NaH (0.8 gram, 20 mmoles).Under room temperature, stirred 10 minutes, be cooled to 0 ℃ then.Add MeI (1.5 milliliters, 24 mmoles), stirred 2 hours, with saturated NH 4Cl makes the stopping of reaction, with ethyl acetate extraction (2x), and with the salt water washing.Make rough thing through the column chromatography purifying, use 20: 1CH 2Cl 2: MeOH, and get product compound 973.
Step B
Figure A0380472003881
In the stirred solution of compound 973 (0.9 gram) in 15 milliliters of THF, add 3 milliliters of 10%LiOH solution, and reactant was stirred 2 days.Evaporating solvent, with methylbenzene azeotropic once, evaporating solvent, and product compound 974.
Step C
Figure A0380472003882
In the stirred solution of compound 974 (about 5.4 mmoles) in 40 milliliters of dry DMF, in room temperature and N 2Add 1.05 grams, 10.8 mmoles (1) down; 2.07 gram, 10.8 mmoles (2); 0.729 gram, 5.4 mmoles (3); And 5.5 milliliters, 50 mmoles (4).Reaction mixture was stirred under room temperature 5 hours.Mat TLC monitoring reaction progress.Add 1NHCl, till pH＜5, with extracted with diethyl ether (2x), be cooled to 0 ℃, then with saturated NaHCO 3Alkalization is with CH 2Cl 2Extraction is with MgSO 4Dry.Evaporating solvent digests compound 975, brown oil and get 0.6.
Step D
In the compound 975 in 5 milliliters of toluene (0.590 gram, 3.2 mmoles), under-70 ℃, dropwise add (3.6 milliliters, 3.6 mmole LAH (1M is in THF)).Reaction mixture under-70 ℃ to-50 ℃ temperature range, was stirred 30 minutes.Make the stopping of reaction with 4 mL of saline, and under room temperature, stirred 20 minutes.Make reactant through the diatomite cake, with vinyl acetic monomer/CH 2Cl 2Wash-out.Make the filtrate drying, evaporating solvent, and get 0.162 gram product (yellow oil), compound 976.
Step e
Figure A0380472003892
As the same procedure of embodiment 510 (steps A), make compound 365a (0.612 gram, 1.25 mmoles) reaction according to basically, but use compound 976 (0.152 gram), preparation compound 977 as intermediate.(yellow solid 0.408 gram).
Step F
If as the same procedure of embodiment 510 (step B), but use compound 977 according to basically, then can prepare compound 978 as initial substance.
Step G
If as the same procedure of embodiment 510 (step C), but use compound 978 according to basically, then can prepare compound 979 as initial substance.
Step H
If as the same procedure of embodiment 510 (step D), but use compound 979 according to basically, then can prepare compound 980 as initial substance.
Step I
If as the same procedure of embodiment 510 (step e), then compound 980 can separate by chirality HPLC, uses chirality OD to prepare the HPLC post, and gets compound 980a and 980b according to basically.
Preparation embodiment 112
Steps A
Figure A0380472003921
Rep.Org.Prep.Preed.Int.(1996)28(6)，709-710.
To 4-iodo-1-trityl-1H-imidazoles (4.36 gram, 10 Bo moles) in THF (100 milliliters) in stirred solution, add EtMgBr (4 milliliters, 12 mmoles), and stirred 30 minutes.Add DMF (0.93 milliliter, 12 mmoles), and stirred 1 hour.Reactant is poured in the saturated ammonium chloride, and extracted with EtOAc.Make organic layer with MgSO 4Drying is filtered, and concentrates under vacuum, and gets 3.5 gram faint yellow solids.
Step B
Figure A0380472003922
As the same procedure of embodiment 510 (steps A), but use compound 981 (0.72 gram) according to basically as intermediate, and MgBrEt 2O (2.58 grams, in 50 milliliters of THF, 7.5 milliliters), obtain crude compound 982.Make plate chromatography purifying (1-3%MeOH and the NH of crude material via preparation 3/ CH 2Cl 2), obtain pure products, compound 982 (0.29,39%).
Step C
Figure A0380472003931
As the same procedure of embodiment 510 (step B), but use compound 982 (0.29 gram) according to basically, preparation compound 983 (0.29 gram) as initial substance.Make crude material via preparation plate chromatography purifying (2%MeOH and NH 3/ CH 2Cl 2), and get 0.237 gram pure products, compound 983.
Step D
As the same procedure of embodiment 510 (step C), but use compound 983 (230 milligrams) according to basically, preparation compound 984 (222 milligrams) as initial substance.
Step e
As the same procedure of embodiment 510 (step D), but use compound 984 (0.2 gram), to make rough isomer 985a and 985b according to basically as initial substance.Make isomer via preparation plate chromatography purifying and separation (5%MeOH and NH 3/ CH 2Cl 2), obtain 0.16 pure 985a of gram and the pure 985b of 0.06 gram.
Preparation embodiment 113
Figure A0380472003942
In the compound 982 (390 milligrams) in being dissolved in THF (3 milliliters), interpolation NaH (60%, in mineral oil, 28 milligrams).After 5 minutes, add methyl iodide, and stirred for several hour.Reactant is concentrated under vacuum, and rough thing is proceeded next reaction.
Preparation embodiment 114
Steps A
Figure A0380472003951
To 987 (2-methyl isophthalic acid H-imidazoles-4-formaldehyde, 1 gram, 9.09 mmoles) in 10 milliliters of DMF in stirred solution, under 0 ℃, portion-wise addition NaH (60%, in Dormant oils (0.36 gram)).Mixture was stirred 1/2 hour, add SEM-Cl (2.02 milliliters, 9.9 mmoles) then.Reaction stirred is till finishing.Reaction mixture is added in the salt solution, and with CH 2Cl 2Extraction (3x).Evaporating solvent obtains oil.Column chromatography (CH 2Cl 2(100%-2%MeOHNH 3/ CH 2Cl 2), obtain 1.68 gram products, compound 988 (77%).
Step B
Figure A0380472003952
As the same procedure of embodiment 510 (steps A), make compound 365a (0.12 gram, 0.25 mmole) reaction according to basically, but use compound 988 (0.1 gram), preparation compound 989 (96 milligrams, 56%) as intermediate.
Step C
As the same procedure of embodiment 510 (step B), but use compound 989 (0.52 gram, 0.79 mmole) according to basically, preparation compound 990 as initial substance.
Step D
As the same procedure of embodiment 510 (step C), but use compound 990 (0.51 gram, 0.79 mmole) according to basically, preparation compound 991 as initial substance.
Step e
Figure A0380472003971
As the same procedure of embodiment 510 (step D), but use compound 991 (0.79 mmole) according to basically, preparation compound 992 as initial substance.
Step F
In the compound 992 in being dissolved in THF (5 milliliters) (0.1 gram), in room temperature and N 2Down, 0.2 milliliter of tetrabutylammonium 1M solution among the interpolation THF (TBAF).Reactant was stirred 2 hours.Add other TBAF (0.2 milliliter), by TLC monitoring reaction.Not reaction after 4 hours.Reactant is handled with 0.5 milliliter of TBAF, and be heated to 85 ℃.After 2 hours, reaction is finished.Make the reactant cooling, and be added in the salt solution, and with CH 2Cl 2Extraction (3x) is with MgSO 4Make the organism drying, filter, and evaporating solvent, and get crude product.Mat preliminary plate chromatography purifying uses 95%CH 2Cl 2/ MeOHNH 3(5%), obtains 0.12 gram product, compound 993.
Step G
If as the same procedure of embodiment 510 (step e), then compound 993 can separate by chirality HPLC, uses chirality OD to prepare the HPLC post, and gets compound 993a and 993b according to basically.
Preparation embodiment 115
Steps A
Figure A0380472003982
In 994 (3.08 grams, 20 mmoles) stirred solution in 15 milliliters of DMF, under 0 ℃, portion-wise addition NaH (60%, in mineral oil, 0.80 gram).After stirred for several minute, add SEM-Cl (3.54 milliliters, 20 mmoles), and reactant stirred spend the night.Salt solution is added in the reactant, and extracts with EtOAc.With organic layer Yi Shui and salt water washing, with MgSO 4Drying is filtered, and concentrates under vacuum.Through hurried formula wash-out column chromatography purifying (CH 2Cl 2/ MeOH, 50: 1 to 20: 1), and get 4.54 gram yellow oils, compound 995.
Step B
Figure A0380472003991
In the stirred solution of compound 995 (3.5 gram) in THF (50 milliliters), add LiOH solution (1M, 24 milliliters), and stirred 2 days.Reaction is not finished; Therefore, add 25 milliliters of MeOH and other 10 milliliters of LiOH solution, and reactant is heated to 40 ℃, heated 2 hours.Reactant is concentrated under vacuum, with methylbenzene azeotropic once, and be evaporated to dried, and compound 996, it is directly continued use, need not to be further purified.
Step C
According to the similar approach described in the preparation embodiment 111 step C, but use compound 996, preparation compound 997 (the rough thing of 5.37 grams).
Step D
According to the similar approach described in the preparation embodiment 111 step D, but use compound 997 (4.2 gram), preparation compound 998.
Preparation embodiment 116
Steps A
Figure A0380472004001
If according to the similar approach described in embodiment 510 (steps A), but use compound 998, then can prepare compound 999 as intermediate.
Step B
Figure A0380472004002
If according to the similar approach described in embodiment 510 (step B), but use compound 999, then can obtain compound 1000.
Step C
If according to the similar approach described in embodiment 510 (step C), but use compound 1000, then can prepare compound 1001 as initial substance.
Step D
Figure A0380472004012
If according to the similar approach described in embodiment 510 (step D), but use compound 1001, then can obtain compound 1002.
Step e
If according to the similar approach described in preparation embodiment 114 (step F), but use compound 1002, then can obtain compound 1003.
Step F
If according to the similar approach described in embodiment 510 (step e), then compound 1003 can separate by chirality HPLC, obtains compound 1003a and 1003b.
Embodiment 1588
According to the similar approach described in embodiment 507, make compound 963a (isomer 1) and compound 963b (isomer 2) change into compound 1004a and compound 1004b.
Figure A0380472004031
Embodiment 1589
According to the similar approach described in embodiment 507, make compound 971a (isomer 1) and compound 971b (isomer 2) change into compound 1005a and compound 1005b.
Figure A0380472004041
Embodiment 1590
According to the similar approach described in embodiment 507, make compound 980a (isomer 1) and compound 980b (isomer 2) change into compound 1006a and compound 1006b.
Embodiment 1591
According to the similar approach described in embodiment 507, make isomer 985a and 985b change into compound 1007a and compound 1007b.
Embodiment 1592
Derive from the preparation embodiment 113 be dissolved in CH 2Cl 2In the product in (5 milliliters), add trifluoracetic acid (1 milliliter), and stirred 1 hour.Reactant is concentrated under vacuum, and rough thing is continued to next reaction.
Figure A0380472004062
Embodiment 1593
According to similar approach, make compound 993a (isomer 1) and compound 993b (isomer 2) change into compound 1009a and compound 1009b as embodiment 507.
Embodiment 1594
If according to the similar approach described in embodiment 507, then compound 1003a (isomer 1) can change into compound 1010a and compound 1010b with compound 1003b (isomer 2).
Figure A0380472004081
Preparation embodiment 117
Steps A
According to the same procedure described in embodiment 510 step C, but use the compound 795 (3 gram) that derives from WO02/18368 embodiment 489, obtain desired crude product (3.3 gram).
Step B
Separate above-mentioned crude material (1011) through hurried formula column chromatography (40%EtOAc/ hexane), and pure isomer A (1011a) (1.23 gram) and pure isomer B (1011b) (1.64 gram) not.Pure isomer B is not in CH 2Cl 2Develop among/the MeOH, and filter, obtain pure isomer 1011b (0.7 gram).
Step C
Figure A0380472004091
Glyoxal ethyline (1.1 gram) is dissolved in the dry DMF (15 milliliters), then adds NaH (60%, in mineral oil, 300 milligrams).After stirring 20 minutes, add compound 1011b (1.2 gram), and this solution is heated to 90 ℃, heated 4 hours.Reactant is concentrated under vacuum, be dissolved in CH 2Cl 2In, and with the salt water washing.Make the organic layer drying, under vacuum, concentrate, and via hurried formula column chromatography purifying (6%MeOH/CH 2Cl 2+ NH 4OH), get desired product (1.47 gram).
Step D
According to the method that proposes among the embodiment 507, make compound 1012 (1.4 gram) change into compound 1013 (1.09 gram).
Preparation embodiment 118
Steps A
Figure A0380472004101
According to the same procedure described in preparation embodiment 117 step C, but use compound 1011a (696 milligrams), obtain desired compound (903 milligrams).
Step B
Figure A0380472004102
According to the method that proposes among the embodiment 507, make compound 1014 (0.9 gram) change into compound 1015 (0.58 gram).
Embodiment 3157-3162
Make from the compound 1015 for preparing embodiment 118 step B
With basically as the reaction of the same way as of embodiment 511-513, and the compound in must table 134.
Table 134
Figure A0380472004121
Embodiment 3163-3168
Make from the compound 1013 for preparing embodiment 117 step D
With basically as the same way as among embodiment 511-513 reaction, and the compound in must table 135.
Table 135
Figure A0380472004141
Figure A0380472004151
Embodiment 3256
Figure A0380472004161
In the THF that remains on 1016 under-78 ℃ (980 milligrams, 2 mmoles) (distillation just, 10 milliliters) solution, dropwise add BuLi (1.6 milliliters, 2.5M hexane solution, 4 mmoles).After 15 minutes, add THF (6 milliliters) solution of 1017 (676 milligrams, 2 mmoles).After stirring 1.5 hours under-78 ℃, at room temperature, make reaction mixture between vinyl acetic monomer and salt solution, make separatory and handle.With water layer once with ethyl acetate extraction.Make the vinyl acetic monomer layer drying of merging, and concentrate in a vacuum.Make formed rough thing use the silicagel column purifying, with ethanol/methylene (2%-5%) wash-out.Obtain compound 1018 (834 milligrams), be faint yellow solid.
At room temperature, compound 1018 (390 milligrams, 0.52 mmole) is dissolved among the THF (3 milliliters).Add NaH (28 milligrams, 60% in mineral oil, 0.7 mmole), after 5 minutes, then add MeI (1.0 milliliters).After stirring 20 hours, in vacuum, it is dried that mixture is evaporated to.Make formed rough thing be dissolved in CH 2Cl 2In (5 milliliters), and add TFA (1 milliliter).After one hour, it is dried that mixture is evaporated to.Make rough thing be dissolved in CH again 2Cl 2In, and by adding triethylamine (about 0.6 milliliter), make PH＞8.Then, add (Boc) 2O (320 milligrams, 1.5 mmoles).Stir after 30 minutes, in vacuum, remove and desolvate, and make residue in CH 2Cl 2And H 2Making separatory between the O handles.Make organic layer dry and concentrated.Use preparation TLC laminate, make rough thing purifying, use 10% methyl alcohol (2MNH 3)/CH 2Cl 2, and get faint yellow solid (121 milligrams).Product is separated through partly preparing the ODHPLC post, with 30%IPA/ hexane/0.2%DEA wash-out, acquisition pure isomer 1019a (44.8 milligrams, isomer 1, MH +=536) with 1019b (53.6 milligrams, isomer 2, MH +=536).
Embodiment 3257
Via at room temperature and N 2Down, with 20%4MHCl (dioxane)/CH 2Cl 2Reaction is spent the night, and makes compound 1019b (isomer 2) change into 1020b.
Use same procedure to prepare 1020a (isomer 1) from 1019a.
Embodiment 3258-3260
Make and be dissolved in CH from each isomer 1020a and the 1020b of embodiment 3257 2Cl 2In.Add TEA, till PH＞8, then add corresponding isocyanate.In case TLC shows the initial substance completely consumed, solvent is concentrated in vacuum.Make residue through silica gel preparative thin layer chromatography method or silica gel chromatography purifying, and get following formula: compound:
Figure A0380472004181
With
Figure A0380472004182
Wherein R is defined in the table 140, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 140
Embodiment 3261-3263
Make and under room temperature and nitrogen, be dissolved in CH from the isomer 1020a of embodiment 3257 2Cl 2In, then add corresponding carboxylic acid and suitable reagent: EDC, HOBT and NMM.Then, the reactant stirring is spent the night, and add 1NHCl till pH=2.Stir after 5 minutes, then with saturated NaHCO 3Make its alkalization, then with CH 2Cl 2Extraction.Organic solvent is concentrated in vacuum, makes residue then, obtain following formula: compound through the silicagel column purifying:
Figure A0380472004191
Wherein R is defined in the table 141, and the 1 expression isomer 1 of the numeral in the formula.
Table 141
Figure A0380472004192
Embodiment 3264
Make and under room temperature and nitrogen, be dissolved in CH from the isomer 1020b of embodiment 3257 2Cl 2In, then add diisopropylethylamine to pH＞8.Then, reactant is handled with its corresponding SULPHURYL CHLORIDE, and under room temperature, stirred, till TLC shows that reaction is finished.Make the stopping of reaction with salt solution, and with CH 2Cl 2Extraction.Make organic layer dry and concentrated.Make residue through the silicagel column purifying, and get following formula: compound:
Figure A0380472004201
Wherein R is defined in the table 142, and the 2 expression isomer 2 of the numeral in the formula.
Table 142
Embodiment 3265-3267
Make isomer 1020b from embodiment 3257 under room temperature and nitrogen, be dissolved in CH 2Cl 2In, then add TEA.Then, reactant is handled with individual chloro-formic ester (according to preparation embodiment 74, system is from its corresponding alcohols) certainly, and under room temperature, stirred, show to react up to TLC and finish.Make the stopping of reaction with salt solution, and with CH 2Cl 2Extraction.Make organic layer dry and concentrated.Make residue through the silicagel column purifying, obtain following formula: compound:
Figure A0380472004211
Wherein R is defined in the table 142, and the 2 expression isomer 2 of the numeral in the formula.
Table 142
Embodiment 3268
Compound 791 is separated through the ADHPLC post,, and get pure isomer 791a (isomer 1, MH with 15%-30%IPA/ hexane/0.2%DEA wash-out +=547.1) with 791b (isomer 2, MH +=547.1).
Embodiment 3269
Via at room temperature and N 2Down, with 20%4MHCl (dioxane)/CH 2Cl 2Reaction is spent the night, and makes compound 791b (isomer 2) change into 1021b.Use same procedure to prepare 1021a (isomer 1) from 791a.
Embodiment 3270
Make and be dissolved in CH from each isomer 1021a and the 1021b of embodiment 3269 2Cl 2In.Adding TEA up to PH＞8, then is its corresponding isocyanate.In case TLC shows the initial substance completely consumed, solvent is concentrated in vacuum.Make residue through silica gel preparative thin layer chromatography method or silica gel chromatography purifying, obtain following formula: compound
With
Figure A0380472004232
Wherein R is defined in the table 144, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 144
Figure A0380472004233
Embodiment 3271
Make from each isomer 1021a and 1021b of embodiment 3269, under room temperature and nitrogen, be dissolved in CH 2Cl 2In, then add corresponding carboxylic acid and suitable reagent: EDC, HOBT and NMM.Then reactant is stirred and spend the night, and add 1NHCl, till pH=2.Stir after 5 minutes, then with saturated NaHCO 3Make its alkalization, then with CH 2Cl 2Extraction.Organic solvent is concentrated in vacuum, makes residue then, obtain following formula: compound through the silicagel column purifying:
With
Wherein R is defined in the table 145, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 145
Figure A0380472004243
Embodiment 3272
Make from each isomer 1021a of embodiment 3269 and 1021b under room temperature and nitrogen, be dissolved in CH 2Cl 2In, then add diisopropylethylamine to PH＞8.Then, reactant is handled with its corresponding SULPHURYL CHLORIDE, and under room temperature, stirred, till TLC shows that reaction is finished.Make the stopping of reaction with salt solution, and with C H2Cl 2Extraction.Make organic layer dry and concentrated.Make residue through the silicagel column purifying, and get following formula: compound:
With
Wherein R is defined in the table 146, and the numeral in chemical formula 1 and 2 is to represent isomer 1 and 2 respectively.
Table 146
Figure A0380472004253
Embodiment 3273
Make from each isomer 1021a and 1021b of embodiment 3269, under room temperature and nitrogen, be dissolved in CH 2Cl 2In, then add TEA.Then, reactant is handled with discrete chloro-formic ester (according to preparation embodiment 74, system is from its corresponding alcohols), and under room temperature, stirred, till TLC shows that reaction is finished.Make the stopping of reaction with salt solution, and with CH 2Cl 2Extraction.Make organic layer dry and concentrated.Make residue through the silicagel column purifying, obtain following formula: compound:
With
Figure A0380472004262
Wherein R is defined in the table 147, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 147
Figure A0380472004263
Embodiment 3274-3277
Figure A0380472004264
Make from embodiment 3268 each isomer, under room temperature and nitrogen, be dissolved among the MeOH, then add excessive SnCl with 3270-3273 2Reactant stirred under room temperature spend the night, concentrate in a vacuum then.Residue was stirred 30 minutes in the mixture of 1NNaOH and vinyl acetic monomer.With ethyl acetate extraction for several times, and with organic layer with the salt water washing.Make the organic layer drying and be evaporated to dried.Make rough thing through the silicagel column purifying, and get following formula: compound:
With
Wherein R is defined in the table 148, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 148
Figure A0380472004281
* the isomer 1 of embodiment 3277 is not made.
Embodiment 3278-3279
According to the method for similar embodiment 3270, make trinitride
Figure A0380472004282
Wherein R is
Or
And the 2 expression isomer 2 of the numeral in the formula.
Then, the method according to similar embodiment 3274 to 3278 prepares the following formula aminocompound from trinitride:
Figure A0380472004291
Wherein R is defined in the table 149, and the 2 expression isomer 2 of the numeral in the formula.
Table 149
Figure A0380472004292
Embodiment 3280
Figure A0380472004301
Make the isomer 2 (70 milligrams, 0.13 mmole) of compound 791 at room temperature, be dissolved in CH 2Cl 2In (5 milliliters).Add TFA (1 milliliter).With reaction mixture in N 2Under stirred 1 hour after, with CH 3It is dried that Ph is evaporated to it.Make residue be dissolved in CH again 2Cl 2In (5 milliliters), and, make solution become pH＞8 by adding triethylamine (about 0.2 milliliter).Then, (0.13 milliliter, 1.0M is in CH dropwise to add isopropyl chlorocarbonate 3Among the Ph).Stir after 1 hour, make the stopping of reaction with water, and with mixture with CH 2Cl 2Extracting twice.Make organic layer dry and concentrated.Make rough thing with preparation TLC laminate purifying, use 10% methyl alcohol (2MNH 3)/CH 2Cl 2, obtain compound 1032, be faint yellow solid (50 milligrams).MSM+1533.
Make compound 1032 (160 milligrams, 0.3 mmole) at room temperature, be dissolved among the MeOH (5 milliliters), and add SnCl 2(150 milligrams, 0.79 mmole).After 3 hours, in vacuum, remove most solvent.In residue, add 30 milliliters of 1NNaOH and 20 milliliters of vinyl acetic monomers.After stirring 20 minutes, turbid solution becomes transparent.With water layer once with ethyl acetate extraction.Make the organic layer of merging dry and concentrated.Make rough thing by preparation TLC laminate purifying, use 10% methyl alcohol (2MNH 3)/CH 2Cl 2, and get compound 1033, be faint yellow solid (90.0 milligrams).Fusing point 132-135 ℃.MSM+1507。
Embodiment 3281
Figure A0380472004311
In the solution of compound 792 (embodiment 486 of WO02/18368) (0.052 gram, 0.1 mmole) in 5 milliliters of anhydrous methylene chlorides, add 0.02 gram triethylamine and 0.01 gram methyl-chloroformate.Stir after two hours, under dry nitrogen, reaction mixture with the salt water washing, and is separated organic phase,, filter also evaporation, obtain crude mixture with dried over mgso.Make crude mixture chromatogram on silica gel, use 10% ethanol/methylene, obtain 0.019 gram end product as eluent.MH+579 (isomer 1) and MH+579 (isomer 2).
Embodiment 3282-3287f
According to the method in the similar embodiment 3281, but use R 9bSubstituent corresponding SULPHURYL CHLORIDE, isocyanic ester, chloro-formic ester or acyl chlorides, the preparation following formula: compound:
With
Figure A0380472004322
R wherein 9bBe defined in the table 150, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.
Table 150
Figure A0380472004323
Embodiment 3288
Figure A0380472004341
In the solution of embodiment 3282 compounds (isomer 2) (150 milligrams), add 10 milliliters of methylene dichloride and 2 milliliters of trifluoracetic acids.Mixture was stirred 1.5 hours, be evaporated to dried then.Make mixture and methylene dichloride azeotropic twice, and be dissolved in again in 15 milliliters of methylene dichloride and the 0.5 milliliter of triethylamine.In the formed compound of 0.08 mmole, add 15 milligrams of isocyanic acid 4-cyanobenzene esters.Reactant was stirred 1 hour, concentrate then.Make residue chromatogram on silica gel, use 10% ethanol/methylene, obtain 0.033 gram product.MH+607 (isomer 2).
Embodiment 3289-3291
According to the method in the similar embodiment 3288, the preparation following formula: compound:
Use the corresponding chloro-formic ester or the isocyanic ester of substituent R, wherein R is defined in the table 151, and the 2 expression isomer 2 of the numeral in the formula.
Table 151
Embodiment 3292-3297
Use the compound (isomer 2) of embodiment 3287, and according to the method in the similar embodiment 3288, the preparation following formula: compound:
Figure A0380472004361
Use corresponding isocyanic ester, SULPHURYL CHLORIDE or the chloro-formic ester of substituent R, wherein R is defined in the table 152, and the 2 expression isomer 2 of the numeral in the formula.
Table 152
Figure A0380472004362
Figure A0380472004371
Embodiment 3298-3302
Use the compound (isomer 2) of embodiment 3285, and according to the method in the similar embodiment 3288, the preparation following formula: compound:
Use corresponding isocyanic ester, SULPHURYL CHLORIDE or the chloro-formic ester of substituent R, wherein R is defined in the table 153, and the 2 expression isomer 2 of the numeral in the formula.
Table 153
Figure A0380472004373
Figure A0380472004381
Embodiment 514-3255
If according to similar embodiment 511-513, or 536, or the method for 566-567 or 590-603, then will obtain the compound of chemical formula hereinafter described, wherein R is defined among the table 153A, and the numeral in the formula 1 and 2 is represented isomer 1 and 2 respectively:
(1) embodiment 514-535,537-544,546-565,568,570-573,575-589 and 604-614, the compound of these embodiment has following chemical formula:
Figure A0380472004382
(2) derive from isomer 897a and 897b: embodiment 615-639,715-732 (consulting the preparation of preparation embodiment 74), 787-814,899,900,902-905,907-913 and 915-922 about chloro-formic ester, the compound of these embodiment has following chemical formula:
(3) derive from isomer 898a and 898b: embodiment 640-664,733-750 (consulting the preparation of preparation embodiment 74), 815-842,923,924,926-929,931-937 and 939-94 about chloro-formic ester, the compound of these embodiment has following chemical formula:
(4) derive from isomer 899a and 899b: embodiment 665-689,751-768 (consulting the preparation of preparation embodiment 74), 843-870,947,948,950-953,955-961 and 963 about chloro-formic ester, the compound of these embodiment is to have following chemical formula:
Figure A0380472004401
(5) derive from isomer 900a and 900b: embodiment 690-714,769-786 (consulting preparation embodiment 74), 871-898,971,973-977,979-985,987 and 989-995 about the preparation of chloro-formic ester, the compound of these embodiment has following chemical formula:
(6) derive from isomer 919a and 919b: embodiment 996-1020,1046-1073,1103-1121 (consulting the preparation of preparation embodiment 74), 1140,1141,1143,1144-1146,1148-1154 and 1156-1163 about chloro-formic ester, the compound of these embodiment has following chemical formula:
Figure A0380472004411
(7) derive from isomer 920a and 920b: embodiment 1021-1045,1075-1102,1122-1139 (consulting the preparation of preparation embodiment 74), 1164-1165,1167-1170,1172-1178 and 1180-1187 about chloro-formic ester, the compound of these embodiment has following chemical formula:
(8) derive from isomer 924a and 924b: embodiment 1188-1212,1239-1266,1296-1313 (consulting the preparation of preparation embodiment 74), 1333-1334,1336-1339,1341-1347 and 1349-1356 about chloro-formic ester, the compound of these embodiment has following chemical formula:
(9) derive from isomer 925a and 925b: embodiment 1213-1221,1223-1238,1267-1294,1315-1332 (consulting the preparation of preparation embodiment 74), 1357-1358,1360-1363,1365-1371 and 1373-1380 about chloro-formic ester, the compound of these embodiment has following chemical formula:
(10) derive from isomer 928a and 928b: embodiment 1381-1405,1432-1459,1432-1459,1488-1505 (consulting the preparation of preparation embodiment 74), 1525-1529,1531,1533-1539 and 1541-1548 about chloro-formic ester, the compound of these embodiment has following chemical formula:
(11) derive from isomer 929a and 929b: embodiment 1406-1409 and 1411-1431,1460-1487,1506-1524 (consulting the preparation of preparation embodiment 74), 1549-1550,1552-1555,1557-1563 and 1565-1572 about chloro-formic ester, the compound of these embodiment is to have following chemical formula:
(12) derive from isomer 1004a and 1004b: embodiment 1595-1619,1620-1647,1648,1650-1654,1656-1660,1662-1671 and 1672-1690 (consulting the preparation of preparation embodiment 74) about chloro-formic ester, the compound of these embodiment is to have following chemical formula:
(13) derive from isomer 1005a and 1005b: embodiment 1691-1715,1716-1743,1744-1745,1747-1750,1752-1758,1760-1767 and 1768-1786 (consulting the preparation of preparation embodiment 74) about chloro-formic ester, the compound of these embodiment has following chemical formula:
Figure A0380472004442
(14) derive from isomer 1006a and 1006b: embodiment 1787 and 1788-1811,1812-1839,1840-1845,1847-1861 and 1862-1880 (consulting the preparation of preparation embodiment 74 about chloro-formic ester), the compound of these embodiment has following chemical formula:
Figure A0380472004451
(15) derive from isomer 1007a and 1007b: embodiment 1881-1905,1906-1933,1935-1940,1942-1956 and 1957-1975 (consulting preparation embodiment 74) about the preparation chloro-formic ester, the compound of these embodiment has following chemical formula:
(16) derive from isomer 1009a and 1009b: embodiment 1976-2000,2001-2028,2028a, 2029-2033,2035-2049 and 2050-2068 (consulting the preparation of preparation embodiment 74) about chloro-formic ester, the compound of these embodiment has following chemical formula:
(17) derive from isomer 1010a and 1010b: embodiment 2069-2093,2094-2099,3000-3021,3022-3027,3029-3043 and 3044-3062 (consulting the preparation of preparation embodiment 74) about chloro-formic ester, the compound of these embodiment has following chemical formula:
Figure A0380472004462
(18) derive from compound 1008: embodiment 3063-3087,3088-3115,3116-3121,3123-3137,3138-3156 (consulting the preparation of preparation embodiment 74) about chloro-formic ester, the compound of these embodiment has following chemical formula:
With
(19) derive from compound 1013 and 1015: embodiment 3169-3187,3188-3215,3216-3221,3223-3237,3237a and 3238-3255 (consulting the preparation of preparation embodiment 74) about chloro-formic ester, the compound of these embodiment has following chemical formula:
Figure A0380472004472
Table 153A
Figure A0380472004491
Figure A0380472004501
Figure A0380472004521
Figure A0380472004531
Figure A0380472004541
Figure A0380472004571
Embodiment 3303-4618
If according to the method for embodiment 3258-3267,3270-3302, use the corresponding isocyanic ester, acyl chlorides, SULPHURYL CHLORIDE or the chloro-formic ester that are defined in the substituent R in the table 154, then will obtain following formula: compound:
With
Wherein R is defined in the table 154, and the numeral in chemical formula 1 and 2 is represented isomer 1 and 2 respectively.In table, " Ex. " expression " embodiment ", and " Compd. " expression " compound ".
Table 154
Figure A0380472004613
Figure A0380472004621
Figure A0380472004631
Figure A0380472004641
Figure A0380472004681
Figure A0380472004701
Figure A0380472004731
Embodiment 4619
Figure A0380472004752
CH to compound 1033 (embodiment 3280) (35 milligrams, 0.07 mmole) 2Cl 2In (5 milliliters) solution, adding 0.03 milliliter of triethylamine, then is that (0.084 milliliter, 1.0M is in CH for isopropyl chlorocarbonate 3Among the Ph, 0.084 mmole).With reactant at room temperature and N 2Under stirred 1 hour.Then, with saturated NaHCO 3Solution makes the stopping of reaction, and with CH 2Cl 2Extracted several times.Make the organic solution drying (MgSO of merging 4), and be evaporated to dried.Make residue by preparing TLC laminate purifying, use 10% methyl alcohol (2MNH 3)/CH 2Cl 2, obtain compound 5001, be pale solid (15.0 milligrams).Fusing point 152-155 ℃ (decomposition).MSM+1593。
Detect
The FPT activity be via measure [ 3H] farnesyl from tetra-sodium [ 3H] the method transesterify is to the biotinylation peptide (vitamin H-CVLS) record derived from the C-end of H-ras.Reaction mixture contains: 50mMTrispH7.7,5mMMgCl 2, 5 μ MZn ++, 5mMDTT, 0.1%Triton-X, 0.05 μ M peptide, people's farnesyl protein transferase of 0.03nM purifying, 0.180 μ M tetra-sodium [ 3H] the method ester, add the tricyclic compound or the vehicle Control thing of specified concentration, cumulative volume is 100 microlitres.In the Vortemp Shaking Incubators, under 37 ℃, 45RPM cultivated 60 minutes, and with the 150 microlitre 0.25MEDTA that contain 0.5%BSA and 1.3 mg/ml streptavidin SPA beads it was stopped with reactant.Radioactivity is in Wallac1450Microbeta liquid scintillation counter vacuum metrics.Suppressing per-cent is to calculate and get with respect to the vehicle Control batch total.
COS cell IC 50(is the detection of basic Chu with cell) is to record according to the detection method described in the WO95/10516 of bulletin on April 20 nineteen ninety-five.GGPTIC 50(inhibition of geranyl geranyl protein transferase, the live body exoenzyme detects), the detection of cell pad biological chemistry and anti-tumor activity (in vivo antitumor research) can record by the detection method described in the WO95/10516.WO95/10516 discloses content and has supplied its reference in this paper.
With various tumour cells (5 * 10 5To 8 * 10 6) be seeded in the flank of big athymia nu/nu female mice of 5-6 week in subcutaneous mode.Use three kinds of tumor models: with the mouse inoblast of H-Ras transformation; The human melanoma cell of HTB-177 human non-small cell lung cancer cell or LOX.Only with the compound treatment in beta-cyclodextrin carrier or the carrier, one day twice (BID) or (QD) once a day 7 days weekly, goes through 1 (x1), 2 (x2) or 3 (x3) weeks with animal.Tumor growth with respect to the mediator control group suppresses per-cent, is to record by tumour tolerance.Its result is reported in the table 155.
Table 155
Compound number Tumour Dosage (MPK) Approach and timetable The average % of tumor suppression
(372) The G-Ras inoblast 40 po，BID，x2 92
″ The H-Ras inoblast 10 po，BID，x2 70
″ The H-Ras inoblast 80 po，QD，x2 91
″ The H-Ras inoblast 20 po，QD，x2 55
″ The H-Ras inoblast 60 po，BID，x2 98
″ The H-Ras inoblast 20 po，BID，x2 59
″ The H-Ras inoblast 6.6 po，BID，x2 19
″ HTB-177 60 po，BID，x3 87
″ HTB-177 20 po，BID，x3 43
″ HTB-177 120 po，QD，x3 54
″ HTB-177 40 po，QD，x3 11
″ HTB-177 80 po，BID，x3 96
″ HTB-177 40 po，BID，x3 79
″ HTB-177 20 po，BID，x3 47
″ LOX 15 po，BID，x1 20.9
″ LOX 30 po，BID，x1 54.8
″ LOX 60 po，BID，x1 90.3
(for example, the timetable of " po, BID, x3 " is meant orally, one day twice, through 7 days (14 times weekly), goes through for 3 weeks).
Soft agar detects:
Do not rely on the make a living feature of oncocyte system of adherent growth.The human tumor cell is suspended in the growth medium of the farnesyl tranfering enzyme inhibitor that contains 0.3% agarose and specified concentration.Can cover growth medium on this solution, it has used 0.6% agarose of the farnesyl tranfering enzyme inhibitor that contains same concentrations to be cured as top layer.At top layer after solidifying, can be with this plate in 37 ℃ and 5%CO 2Down, cultivated 10-16 days, to allow colony to outgrowth.After cultivating, can cover agar via solution (1 mg/ml is in PBS) with MTT (bromination 3-[4,5-dimethyl-thiazol-2-yl]-2,5-phenylbenzene tetrazolium, thiazolyl indigo plant), make bacterium colony dyeing.The count enable colony, and can measure IC 50
Some The compounds of this invention has FPTIC 50In the scope of 0.05nM to 100nM, and soft agar IC 50In the scope of＜0.5nM to 50nM.
Embodiment 4916 compounds have FPTIC 50Be 1.2nM, and soft agar IC 50For＜0.5nM.
For from compound of the present invention for pharmaceutical compositions, the pharmaceutically acceptable carrier of inertia can be solid or liquid.But the solid form preparation comprises pulvis, tablet discrete particles, capsule, cachet and suppository.Powder and tablet can comprise about 5 active ingredients to about 95 per-cents.Suitably solid carrier is known in the art, for example magnesiumcarbonate, Magnesium Stearate, talcum, sugar or lactose.Tablet, pulvis, cachet and capsule can be used as the solid dosage that is suitable for oral administration and use.The embodiment of pharmaceutically acceptable carrier, and the method for making of various compositions can consult A.Gennaro (writing), Remington: pharmacy science and practice, the 20th edition (2000), LippincottWilliams﹠amp; Wilkins, Baltimore, MD.
Liquid form preparation comprises solution, suspension and emulsion.Can point out followingly as embodiment, water or water-propylene glycol solution are used for the injection of non-stomach and intestine, or add sweetener and opalizer, are used for oral liquid, suspension and emulsion.Liquid form preparation also can comprise the solution for intranasal administration.
Be applicable to the aerosol preparations of suction, can comprise solution and be the solid of powder type, its can with pharmaceutically acceptable carrier, such as inertia pressurized gas, for example nitrogen merges.
Also comprise the solid form preparation, it was intended to before using to be converted to liquid form preparation, for oral or parenteral introduction soon.This kind liquid form comprises solution, suspension and emulsion.
The compounds of this invention can also transmit through the skin mode.Transdermal composition can be taked the form of emulsifiable paste, lotion, aerosol and/or emulsion, and can be comprised in pasting in the medicine through skin of matrix or reservoir type, and it is the commonly used of this purpose in this area.
This compound is preferably with the oral way administration.
This pharmaceutical preparation preferably is unit dosage.In this kind form, preparation is subdivided into the unitary dose of suitable size, contains the active ingredient of appropriate amount, for example for reach institute's syllabus significant quantity.
The amount of active compound in unit dose formulations can change or adjust, from about 0.01 milligram to about 1000 milligrams, be preferably about 0.01 milligram to about 750 milligrams, more preferably about 0.01 milligram to about 500 milligrams, and most preferably be about 0.01 milligram to about 250 milligrams, decide according to application-specific.
The actual dose that is adopted can change according to patient's requirement and by the seriousness of treatment symptom.To the mensuration of the suitable dosage taking method of particular condition, in those skilled in the art's limit of power.For simplicity, total day clothes dosage can be distinguished, and gradation is used in during one day, decides on demand.
The dosage of The compounds of this invention and/or its pharmaceutically-acceptable salts and frequency are that the judgement according to the clinicist adjusts, and consider some factors, such as patient's age, symptom and size, and by the seriousness of treatment symptom.Typical case to oral administration recommends dosage taking method every day, and its scope can be about 0.04 mg/day to about 4000 mg/day, in two to four parts of separate dose.
Chemotherapeutic and/or radiotherapy can be followed the administration together of outstanding The compounds of this invention, and according to the dosage and the administration time table that are listed in the list of the permission medicament product information in the bibliography (PDR) on doctor's table, and this area treatment doubtful case known is carried out.Dosage and dosage taking method are schematically illustrated in the specific embodiments of the present invention.Can be used for the dosage of chemotherapeutic of the present invention and other embodiment of dosage taking method, be shown in the table 156.
Table 156
The dosage and the dosage taking method of chemotherapeutic for example
Cis-platinum: the 50-100 milligram/square metre, (IV) * of per 4 weeks
Carboplatin: the 300-360 milligram/square metre, per 4 weeks (IV)
Taxotere: the 60-100 milligram/square metre, per 3 weeks (IV)
* (IV)-intravenously mode
Those skilled in the art it is evident that, chemotherapeutic and/or radiotherapeutic administration can be according to by the diseases of being treated, and chemotherapeutic and/or radiotherapy change the known action of this disease.And, knowledge according to the clinicist, treatment doubtful case (for example dosage of administration and number of times) can in view of using chemotherapeutic (meaning is antineoplastic agent or radiation) to the effect that the patient found, and the institute of institute's administering therapeutic agent found to react and change in view of disease.
In the combination treatment embodiment of treatment carcinoma of the pancreas, (meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example) be with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose, follow outstanding antineoplastic agent gemcitabine, it is administration under 750 to 1350 milligrams/square metre dosage, weekly, three weeks in during therapeutic process, going through all around.
In the combination treatment embodiment of treatment lung cancer, (meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example) be with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose, follow outstanding antineoplastic agent taxol, it is administration under 65 to 175 milligrams/square metre dosage, and per three weeks once.
In the gliomatous combination treatment embodiment of treatment, fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula (1.0) compound) is with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose; Follow not Lip river acid amides (temozolomide) of outstanding antineoplastic agent sky, it is administration under 100 to 250 milligrams/square metre dosage.
In another embodiment of the combination treatment for the treatment of cancer, (meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example) be with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose, follow outstanding antineoplastic agent cis-platinum, it is with the administration of intravenously mode, in 50 to 100 milligrams/square metre scope, whenever all around once.
In another embodiment of the combination treatment for the treatment of cancer, (meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example) be with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose, follow outstanding antineoplastic agent carboplatin, it is with the administration of intravenously mode, the 300-360 milligram/square metre scope in, every around once.
In another embodiment of the combination treatment for the treatment of cancer, (meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example) be with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose, follow outstanding chemotherapeutic carboplatin, it is with the administration of intravenously mode, in 300 to 360 milligrams/square metre scope, whenever all around once, and the chemotherapeutic taxol, it is administration under 65 to 175 milligrams/square metre dosage, per three weeks are once.
In another embodiment of the combination treatment for the treatment of cancer, (meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example) be with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose, follow outstanding chemotherapeutic cis-platinum, it is with the administration of intravenously mode, in 50 to 100 milligrams/square metre scope, whenever all around once, and the chemotherapeutic gemcitabine, it is administration under 65 to 175 milligrams/square metre dosage, per three weeks are once.
Signal transduction suppresses therapy can be according to the dosage and the administration time table that are listed in the product information of permission medicament is single in the bibliography (PDR) on doctor's table, and administration is carried out in this area treatment doubtful case known.The embodiment of the dosage of some signal transduction inhibitors and dosage taking method scope is shown in the following table 157.
Table 157
The dosage and the dosage taking method of signal transduction inhibitor for example
Iressa (ZD1839)-EGF receptor kinase inhibitor: 150-700 mg/day (oral)
OSI-774-EGF receptor kinase inhibitor: 100-1000 mg/day (oral)
Herceptin (trastuzumab)-HER-2/neu antibody: the 100-250 milligram/square metre/week (IV) *
The C225-EGF receptor antibody: the 200-500 milligram/square metre/week (IV)
ABX-EGF-EGF receptor antibody: per 2 weeks of 0.2-2 milligram/kilogram (IV)
Gleevec (imatinib mesylate) (STI-571)-bcr/abl 300-1000 mg/day (oral)
Kinase inhibitor:
* (IV)-intravenously mode
Those skilled in the art it is evident that, the administration of signal transduction inhibitor can be according to the disease of being treated, and the signal transduction inhibitor therapy changes the known action of this disease.And, according to clinicist's knowledge, treatment doubtful case (for example dosage of administration and number of times), can in view of using signal transduction inhibitor to the effect that the patient found, and the reaction of institute's administering therapeutic agent being found in view of this disease and changing.
In another embodiment of the combination treatment for the treatment of cancer, (meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example) be with the oral way administration, in the scope of 50 to 400 mg/day, in two separate dose, follow outstanding signal transduction inhibitor EGF receptor kinase inhibitor Iressa (ZD1839), it is with the oral way administration, in the scope of 150-700 mg/day.
Fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula (1.0) compound), chemotherapeutic, signal transduction inhibitor and/or radiation can be via the different approaches administrations.For example, fpt inhibitor can the oral way administration, and chemotherapeutic can the administration of intravenously mode.Initial administration can have been set up doubtful case and implemented according to known in the art, and dosage, mode of administration and administration number of times can be revised by the clinicist by the basic Chu that act as to be found then.
The specific selection of chemotherapeutic, signal transduction inhibitor and/or the radiation of using with fpt inhibitor of the present invention is to decide with suitable treatment doubtful case according to the diagnosis of being responsible for the doctor and to the judgement of patient's symptom.
(meaning is a The compounds of this invention to fpt inhibitor of the present invention, formula (1.0) compound for example), chemotherapeutic, signal transduction inhibitor and/or radiation, (in for example simultaneously, just before or after the identical treatment doubtful case, or during it) or administration one after the other side by side.The decision of order of administration can be measured by the clinicist.The clinicist can be in order to some factors of decision treatment doubtful case, character for proliferative disease, patient's symptom, and the actual selection of chemotherapeutic, signal transduction inhibitor and/or the radiation of desire and fpt inhibitor Combined Preparation (meaning is promptly in the single therapy doubtful case).
(meaning is a The compounds of this invention as if fpt inhibitor of the present invention, formula (1.0) compound for example), chemotherapeutic, signal transduction inhibitor and/or radiation, it is not administration simultaneously, then at first administration of fpt inhibitor, then use chemotherapeutic, signal transduction inhibitor and/or radiation, or chemotherapeutic, signal transduction inhibitor and/or at first administration of radiation, then use fpt inhibitor.This replaces administration and can repeat during the single therapy doubtful case, till finishing this treatment doubtful case.During the treatment doubtful case, the decision of the order of administration of each therapeutical agent and administration multiplicity after the symptom of assessing the disease treated and patient, is well in the ken of skilled practitioners.
Therefore, rule of thumb with knowledge, when treatment is carried out, carrying out the doctor can be according to the needs of individual patient, modification is used for each doubtful case of administering therapeutic composition (therapeutical agent-Yi is fpt inhibitor of the present invention (meaning is a The compounds of this invention, for example formula (1.0) compound), chemotherapeutic, signal transduction inhibitor or radiation).
Be responsible for the clinicist, judge treatment whether effectively the time, will consider patient's general health, and clearer and more definite symptom at the dosage of being used, such as the alleviating of disease related symptom, the inhibition of tumor growth, the actual inhibition of dwindling or shifting of tumour.The big I of tumour is measured by standard method, such as radiology research, for example CAT or MRI scanning, and can use continuous measure whether to be slowed down or even reverse to judge growth of tumor.Alleviating of disease related symptom such as pain, and the improvement of whole symptom also can be in order to help to judge the validity of treatment.
The other drug of specific embodiments of the present invention and methods of treatment are described in hereinafter.
A specific embodiments of the present invention relates to a kind of pharmaceutical composition, and it comprises the The compounds of this invention of significant quantity, with pharmaceutically acceptable carrier.
A specific embodiments of the present invention relates to a kind of pharmaceutical composition, and it comprises formula 1.0 compounds of significant quantity, with pharmaceutically acceptable carrier.
A specific embodiments of the present invention relates to a kind of pharmaceutical composition, and it comprises formula 1.4 compounds of significant quantity, with pharmaceutically acceptable carrier.
A specific embodiments of the present invention relates to a kind of method for the treatment of abnormal growth of cells in the patient of needs treatment, and it comprises the The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, and it comprises the The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity.
A specific embodiments of the present invention relates to a kind of method for the treatment of the tumour of expressing activation ras oncogene in the patient of needs treatment, and it comprises the The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, wherein this tumour is selected from: pancreatic neoplasm, lung tumor, myeloid leukemia, Tiroidina filter palpebral edema knurl, myelodysplastic syndrome, head and tumor colli, melanoma, breast tumor, tumor of prostate, ovarian tumor, tumor of bladder, neurospongioma, epidermis tumour and colon tumor, it comprises the The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity.
A specific embodiments of the present invention relates to a kind of method that suppresses the ras farnesyl protein transferase in the patient of needs treatment, and it comprises the The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, wherein Ras protein is that it comprises the The compounds of this invention (for example formula 1.0 compounds) of this patient being used significant quantity owing to the sudden change of the carinogenicity in the gene beyond the Ras gene is activated.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, wherein this tumour is selected from: pancreatic neoplasm, the lungs tumour, myeloid leukemia, Tiroidina filter palpebral edema knurl, myelodysplastic syndrome, head and tumor colli, melanoma, breast tumor, tumor of prostate, ovarian tumor, tumor of bladder, neurospongioma, epidermis tumour and colon tumor.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, wherein this tumour is selected from lung cancer, head and neck cancer, bladder cancer, mammary cancer, prostate cancer and myeloid leukemia.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, at least a chemotherapeutic and/or radiation with significant quantity, wherein this chemotherapeutic is an antineoplastic agent, and described antineoplastic agent is selected from: NSC-34462, chlormethine, endoxan, Yi Fasi acid amides (ifosfamide), phenyalamine mustard, Chlorambucil (Chlorambucil), pipobroman, Persistol, triethylene sulfo-phosphamidon, busulfan, Carmustine, lomustine, strepto-nitroso-group element, dacarbazine, it is Lip river acid amides (temozolomide) not, methotrexate, 5 FU 5 fluorouracil, floxuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, not reach Rabin (fludarabine) phosphoric acid salt, penta holder system rhzomorph (pentostatin), gemcitabine, vincaleucoblastine, vincristine(VCR), Vincamine, bleomycin, the Da Keting mycin, daunorubicin, many gram Suo Hong rhzomorphs, show red rhzomorph, according to reaching red rhzomorph, taxol, taxotere, mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, Interferon, rabbit, clothing holder glucosides (etoposide), the female alcohol of they Buddhist nun's glycosides 17 alpha-acetylenes, stilboestrol, testosterone, prednisone, FL, Zhuo Moshitan ketone (Dromostanolone) propionic salt, the testis lactones, the megestrol acetic ester, tamoxifen, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium, female Maas spit of fland (estramustine), the Zytron acetic ester, stay general lactone (leuprolide), not as acid amides (flutamide), Tuoli rice fen (toremifene), Guo She Rayleigh (goserelin), cis-platinum, carboplatin, hydroxyurea, A Musa element (amsacrine), procarbazine, mitotane, silk splits flavones (mitoxantrone), L-tetramisole, that prestige is (Navelbene) also, CPT-11, At history azoles (Anastrazole), row are arranged azoles (letrazole), card is joined Xi Tabin (capecitabine), Rui Luosha fen (Reloxafine), Zhuo Luosha fen (Droloxafine) and altretamine.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, at least a chemotherapeutic and/or radiation with significant quantity, wherein this chemotherapeutic is that microtubule influences agent, is selected from other colchicine, Harry chrondroitin B, colchicine, colchicine derivative, Duola makes rhzomorph 10, maytansine, the sharp element (rhizoxin) of sitting, taxol, D51-7059, taxotere, the sulfenyl colchicine, the trityl aminothiopropionic acid, vincaleucoblastine vitriol, leucocristine sulfate, Ai Pu Shillong A, Ai Boxi ketone (Epothilone), Di Sikede lactone (discodermolide), female Maas spit of fland (estramustine), Nuo Keda azoles (nocodazole) and MAP4.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, wherein this chemotherapeutic is selected from gemcitabine, cis-platinum, carboplatin, taxol, D51-7059 and taxotere.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises formula 1.0 compounds of co-administered significant quantity simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, its Chinese style 1.0 compounds are selected from:
Figure A0380472004861
Figure A0380472004871
Figure A0380472004881
With
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, compound wherein of the present invention is selected from:
Figure A0380472004911
With
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises formula 1.0 compounds of co-administered significant quantity simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, its Chinese style 1.0 compounds are selected from:
Figure A0380472004942
With
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises formula 1.0 compounds of co-administered significant quantity simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, its Chinese style 1.0 compounds are selected from:
Figure A0380472004952
With
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises formula 1.0 compounds of co-administered significant quantity simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, its Chinese style 1.0 compounds are selected from:
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, wherein the tumour of being treated is selected from: lung cancer, head and neck cancer, bladder cancer, mammary cancer, prostate cancer and myeloid leukemia; Wherein chemotherapeutic is selected from: taxol, D51-7059, taxotere, endoxan, 5 FU 5 fluorouracil, sky be Lip river acid amides, vincristine(VCR), cis-platinum, carboplatin and gemcitabine not.
A specific embodiments of the present invention relates to a kind of method for the treatment of lung cancer in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, wherein chemotherapeutic is selected from: carboplatin, taxol and taxotere.
A specific embodiments of the present invention relates to a kind of method for the treatment of lung cancer in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a chemotherapeutic and/or the radiation of significant quantity, wherein chemotherapeutic is selected from: gemcitabine and cis-platinum.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with the taxol and/or the radiation of significant quantity, wherein the tumour of being treated is selected from: lung cancer, head and neck cancer, bladder cancer, mammary cancer, prostate cancer and myeloid leukemia.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a signal transduction inhibitor of significant quantity.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises at least a signal transduction inhibitor of the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) and significant quantity simultaneously or in succession to this patient, and wherein tumour is selected from: pancreatic neoplasm, lung tumor, myeloid leukemia, Tiroidina filter palpebral edema knurl, myelodysplastic syndrome, head and tumor colli, melanoma, breast tumor, tumor of prostate, ovarian tumor, tumor of bladder, neurospongioma and colon tumor.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a signal transduction inhibitor of significant quantity, wherein signal transduction inhibitor is selected from: bcr/abl kinase inhibitor, epidermal growth factor receptor inhibitor and HER-2/neu acceptor inhibitor.
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a signal transduction inhibitor of significant quantity, wherein signal transduction inhibitor is selected from: Gleevec (imatinib mesylate), Iressa, OSI-774, clothing nurse clone (Imclone) C225, hard Nice (Abgenix) ABX-EGF of Abel and Herceptin (trastuzumab).
A specific embodiments of the present invention relates to a kind of method for the treatment of tumour in the patient of needs treatment, it comprises the The compounds of this invention of co-administered significant quantity (for example formula 1.0 compounds) simultaneously or in succession to this patient, with at least a signal transduction inhibitor of significant quantity, wherein the tumour of being treated is selected from: lung tumor, head and tumor colli, tumor of bladder, breast tumor, tumor of prostate and myeloid leukemia; And signal transduction inhibitor is selected from: Gleevec (imatinib mesylate), Iressa, OSI-774, clothing nurse clone (Imclone) C225, hard Nice (Abgenix) ABX-EGF of Abel and Herceptin (trastuzumab).
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; Or
(13) α V β 3 integrates plain micromolecular inhibitor;
(14) folate antagonist;
(15) ribonucleotide reductase inhibitor;
(16) anthracycline antibiotics;
(17) biological product;
(18) Thalidomide (or relevant imide); And
(19) Gleevec (imatinib mesylate).
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; Or
(13) α V β 3 integrates plain micromolecular inhibitor;
(14) folate antagonist;
(15) ribonucleotide reductase inhibitor;
(16) anthracycline antibiotics;
(17) biological product; And
(18) Thalidomide (or relevant imide).
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; Or
(13) α V β 3 integrates plain micromolecular inhibitor;
(14) folate antagonist;
(15) ribonucleotide reductase inhibitor;
(16) anthracycline antibiotics; And
(17) biological product.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; And
(13) α V β 3 integrates plain micromolecular inhibitor.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this Taxan is selected from taxol or docetaxel, and this iridium-platinum complex is selected from carboplatin or cis-platinum.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this Taxan is a taxol, and this iridium-platinum complex is a carboplatin.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this Taxan is a taxol, and this iridium-platinum complex is a cis-platinum.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this Taxan is a docetaxel, and this iridium-platinum complex is a cis-platinum.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this Taxan is a docetaxel, and this iridium-platinum complex is a carboplatin.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, wherein this Taxan is a taxol, with about 150 milligrams to about 250 milligrams/square metre amount phase in per three weeks are administered once weekly, and this iridium-platinum complex is a carboplatin, is that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, wherein this Taxan is a docetaxel, with about 50 milligrams to about 100 milligrams/square metre amount phase in per three weeks are administered once weekly, and this iridium-platinum complex is a cis-platinum, with about 60 milligrams to about 100 milligrams/square metre amount phase in per three weeks are administered once weekly.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is with about 75 milligrams of extremely about 125 milligrams amount one day administered twice.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is selected from:
Figure A0380472005031
Figure A0380472005051
With
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of the present invention of this patient being used significant quantity, and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is selected from:
Figure A0380472005061
Figure A0380472005071
With
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is selected from:
Figure A0380472005081
Figure A0380472005102
With
Figure A0380472005103
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of the present invention of this patient being used significant quantity, and two kinds of antineoplastic agents, wherein an antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is selected from:
Figure A0380472005111
Figure A0380472005121
With
Figure A0380472005122
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is:
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein an antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is:
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this fpt inhibitor is:
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, wherein the treatment be weekly give the phase one to around.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, wherein is the treatment nonsmall-cell lung cancer.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is the EGF inhibitor, and it is an antibody.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is the EGF inhibitor, and it is an antibody, wherein this Taxan is a taxol, and this EGF inhibitor is Herceptin (trastuzumab).
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is anti-nucleoside derivates, and another kind of antineoplastic agent is an iridium-platinum complex.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is anti-nucleoside derivates, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this anti-nucleoside derivates is a gemcitabine, and this iridium-platinum complex is a cis-platinum.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is anti-nucleoside derivates, and another kind of antineoplastic agent is an iridium-platinum complex, and wherein this anti-nucleoside derivates is a gemcitabine, and this iridium-platinum complex is a carboplatin.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) taxol.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) taxol,
Wherein this fpt inhibitor is one day administered twice, and this carboplatin is administered once weekly in phase in per three weeks, and this taxol is weekly to be administered once in phase in per three weeks, this treatment be weekly give the phase one to around.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) taxol,
Wherein this fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided, this taxol is that phase in per three weeks are administered once weekly to about 250 milligrams/square metre amount with about 150, wherein this carboplatin and this taxol are in administration on the same day, and this treatment be weekly give the phase one to around.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) taxol,
Wherein this fpt inhibitor is with about 75 milligrams of extremely about 125 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided, this taxol is that phase in per three weeks are administered once weekly to about 250 milligrams/square metre amount with about 150, this carboplatin and this taxol are in administration on the same day, and this treatment be weekly give the phase one to around.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) taxol,
Wherein this fpt inhibitor is with about 100 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided, this taxol is that phase in per three weeks are administered once weekly to about 250 milligrams/square metre amount with about 150, wherein this carboplatin and this taxol are in administration on the same day, and this treat weekly the phase give one to around.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) taxol,
Wherein this fpt inhibitor is with about 100 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided, this taxol is that phase in per three weeks are administered once weekly to about 225 milligrams/square metre amount with about 175, wherein this carboplatin and this taxol are in administration on the same day, and this treatment be weekly give the phase one to around.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) taxol,
Wherein this fpt inhibitor is with about 100 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 6 amount so that AUC to be provided, this taxol is that phase in per three weeks are administered once weekly with about 175 milligrams/square metre amount, wherein this carboplatin and this taxol are in administration on the same day, and this treat weekly the phase give one to around.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With:
(b) cis-platinum; And
(c) gemcitabine.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With:
(b) cis-platinum; And
(c) gemcitabine,
Wherein this fpt inhibitor is one day administered twice, and this cis-platinum is weekly the phase per three or is administered once all around, and this gemcitabine is weekly to be administered once in one week of phase, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With:
(b) cis-platinum; And
(c) gemcitabine,
Wherein this fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, this cis-platinum is to about 100 milligrams/square metre amount phase per three or be administered once all around weekly with about 60, this gemcitabine is to be administered once in one week of phase weekly to about 1250 milligrams/square metre amount with about 750, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With:
(b) cis-platinum; And
(c) gemcitabine,
Wherein this fpt inhibitor is with about 75 milligrams of extremely about 125 milligrams amount one day administered twice, this cis-platinum is to about 100 milligrams/square metre amount phase per three or be administered once all around weekly with about 60, this gemcitabine is to be administered once in one week of phase weekly to about 1250 milligrams/square metre amount with about 750, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With:
(b) cis-platinum; And
(c) gemcitabine,
Wherein this fpt inhibitor is with about 100 milligrams amount one day administered twice, this cis-platinum is to about 100 milligrams/square metre amount phase per three or be administered once all around weekly with about 60, and this gemcitabine is to be administered once in one week of phase weekly to about 1250 milligrams/square metre amount with about 750, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) gemcitabine.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) gemcitabine,
Wherein this fpt inhibitor is one day administered twice, and this carboplatin is weekly to be administered once in phase in per three weeks, and this gemcitabine is weekly to be administered once in one week of phase, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) gemcitabine,
Wherein this fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided, this gemcitabine is to be administered once in one week of phase weekly to about 1250 milligrams/square metre amount with about 750, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) gemcitabine,
This treatment is weekly to give for one to seven week the phase, wherein this fpt inhibitor is with about 75 milligrams of extremely about 125 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided, and this gemcitabine is to be administered once in one week of phase weekly to about 1250 milligrams/square metre amount with about 750, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) gemcitabine,
Wherein this fpt inhibitor is with about 100 milligrams amount one day administered twice, this carboplatin is to be that phase in per three weeks are administered once weekly for about 5 to about 8 amount so that AUC to be provided, this gemcitabine is to be administered once in one week of phase weekly to about 1250 milligrams/square metre amount with about 750, and this is treated weekly the phase and gave for one to seven week.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of significant quantity formula 1.4F on this patient's administering therapeutic (1.4F for example, wherein X is N) and antineoplastic agent, described antineoplastic agent is selected from:
(1) EGF inhibitor, it is an antibody;
(2) EGF inhibitor, it is a small molecules;
(3) VEGF inhibitor, it is an antibody; Or
(4) VEGF kinase inhibitor, it is a small molecules.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of significant quantity formula 1.4F on this patient's administering therapeutic (1.4F for example, wherein X is N) and antineoplastic agent, described antineoplastic agent is selected from: Herceptin (trastuzumab), Cetuximab (Cetuximab), Ta Xifa (Tarceva), Iressa, rhuMAb-VEGF, IMC-1C11, SU5416 and SU6688.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of significant quantity formula 1.4F on this patient's administering therapeutic (1.4F for example, wherein X is N) and antineoplastic agent, described antineoplastic agent is selected from:
(1) EGF inhibitor, it is an antibody;
(2) EGF inhibitor, it is a small molecules;
(3) VEGF inhibitor, it is an antibody; Or
(4) VEGF kinase inhibitor, it is a small molecules,
Wherein fpt inhibitor is one day administered twice, this antineoplastic agent, it is an antibody, one week of phase is administered once weekly, and this antineoplastic agent, it is a small molecules, administration every day, this treat weekly the phase give one to around.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of significant quantity formula 1.4F on this patient's administering therapeutic (1.4F for example, wherein X is N) and antineoplastic agent, described antineoplastic agent is selected from:
(1) EGF inhibitor, it is an antibody;
(2) EGF inhibitor, it is a small molecules;
(3) VEGF inhibitor, it is an antibody; Or
(4) VEGF kinase inhibitor, it is a small molecules,
Wherein this fpt inhibitor is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, with this antineoplastic agent, it is an antibody, one week of phase is administered once weekly to about 10 milligrams/square metre amount with about 2, and this antineoplastic agent, it is a small molecules, with about 50 to about 2400 milligrams/square metre amount administration every day, and this treat weekly the phase give one to around.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of significant quantity formula 1.4F on this patient's administering therapeutic (1.4F for example, wherein X is N) and antineoplastic agent, described antineoplastic agent is selected from:
(1) EGF inhibitor, it is an antibody;
(2) EGF inhibitor, it is a small molecules;
(3) VEGF inhibitor, it is an antibody; Or
(4) VEGF kinase inhibitor, it is a small molecules,
Wherein this fpt inhibitor is with about 75 milligrams of extremely about 125 milligrams amount one day administered twice, with this antineoplastic agent, it is an antibody, one week of phase is administered once weekly to about 10 milligrams/square metre amount with about 2, and this antineoplastic agent, it is a small molecules, is with about 50 to about 2400 milligrams/square metre amount administration every day, and this treat weekly the phase give one to around.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound of significant quantity formula 1.4F on this patient's administering therapeutic (1.4F for example, wherein X is N) and antineoplastic agent, described antineoplastic agent is selected from:
(1) EGF inhibitor, it is an antibody;
(2) EGF inhibitor, it is a small molecules;
(3) VEGF inhibitor, it is an antibody; Or
(4) VEGF kinase inhibitor, it is a small molecules,
This treatment be weekly give the phase one to around, wherein this fpt inhibitor is with about 100 milligrams amount one day administered twice, with this antineoplastic agent, it is an antibody, be to be administered once in one week of phase weekly to about 10 milligrams/square metre amount with about 2, and this antineoplastic agent, it is a small molecules, be with about 50 to about 2400 milligrams/square metre amount administration every day, and this treat weekly the phase give one to around.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, wherein this Taxan is a taxol, with about 150 milligrams to about 250 milligrams/square metre amount one week of phase is administered once weekly, and this iridium-platinum complex is a carboplatin, is that one week of phase is administered once weekly for about 5 to about 8 amount so that AUC to be provided.
A specific embodiments of the present invention relates to a kind ofly treats method for cancer in the patient of needs treatments, it comprises the fpt inhibitor compound (1.4F for example that this patient is used significant quantity formula 1.4F, wherein X is N), and two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex, wherein this Taxan is a docetaxel, with about 50 milligrams to about 100 milligrams/square metre amount one week of phase is administered once weekly, and this iridium-platinum complex is a cis-platinum, with about 60 milligrams of extremely about 100 milligrams/square metre amount administrations.
A specific embodiments of the present invention relates to a kind of method for the treatment of nonsmall-cell lung cancer in the patient of needs treatment, and it comprises the following material to significant quantity on this patient's administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) carboplatin; And
(c) docetaxel.
A specific embodiments of the present invention relates to a kind of method for the treatment of head and neck squamous cell cancer in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N); With
(b) one or more antineoplastic agent, it is selected from:
(1) taxanes; With
(2) iridium-platinum complex.
A specific embodiments of the present invention relates to a kind of method for the treatment of head and neck squamous cell cancer in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) at least two kinds of different antineoplastic agents, it is selected from:
(1) taxanes;
(2) iridium-platinum complex; And
(3) antitumor nucleoside derivates (for example 5 FU 5 fluorouracil).
A specific embodiments of the present invention relates to a kind of method for the treatment of CML in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) Gleevec (imatinib mesylate); And
(c) Interferon, rabbit (for example Intron-A).
A specific embodiments of the present invention relates to a kind of method for the treatment of CML in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) Gleevec (imatinib mesylate); And
(c) Interferon, rabbit of PEGization (for example PEG-Intron and Pegasys).
A specific embodiments of the present invention relates to a kind of method for the treatment of AML in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) antitumor nucleoside derivates (for example cytosine arabinoside (meaning is Ara-C)).
A specific embodiments of the present invention relates to a kind of method for the treatment of AML in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) antitumor nucleoside derivates (for example cytosine arabinoside (meaning is Ara-C)); And
(c) anthracycline antibiotics.
A specific embodiments of the present invention relates to a kind of method for the treatment of non-Hodgkin lymphoma in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) Rituximab (Rituximab) (Rituxan).
A specific embodiments of the present invention relates to a kind of method for the treatment of non-Hodgkin lymphoma in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) Li Tuximabai (Rituxan); And
(c) antitumor nucleoside derivates (for example not reaches Rabin (fludarabine) (meaning is F-ara-A).
A specific embodiments of the present invention relates to a kind of method for the treatment of non-Hodgkin lymphoma in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) Genasense (BCL-2 is had antisense).
A specific embodiments of the present invention relates to a kind of method for the treatment of multiple myeloma in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) proteoplast inhibitor (for example PS-341 (Millenium)).
A specific embodiments of the present invention relates to a kind of method for the treatment of multiple myeloma in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) Thalidomide or relevant imide.
A specific embodiments of the present invention relates to a kind of method for the treatment of multiple myeloma in the patient of needs treatment, and it comprises the following material of significant quantity on the administering therapeutic:
(a) fpt inhibitor of formula 1.4F (for example 1.4F, wherein X is N);
(b) Thalidomide.
Other specific embodiments of the present invention relate to the fpt inhibitor (1.4F for example of above-mentioned use formula 1.4F, wherein X is N) specific embodiments, wherein except using fpt inhibitor and antineoplastic agent, also before the treatment cycle, during or afterwards, use radiotherapy.
To using the specific embodiments of the present invention of formula 1.4F compound (for example 1.4F, wherein X is N), formula 1.4F compound is preferably selected from:
Figure A0380472005241
Figure A0380472005251
Figure A0380472005261
With
More preferably be selected from:
Figure A0380472005271
With
Most preferably be:
Figure A0380472005294
With
Again more preferably
Figure A0380472005301
In other specific embodiments of the present invention, the The compounds of this invention beyond the formula 1.4F is with about using the described same way as of formula 1.4F compound to use, and in these other specific embodiments, compound is preferably selected from:
Figure A0380472005302
With With
More preferably be selected from:
Figure A0380472005323
Figure A0380472005331
With
Though the present invention has followed particular proposed above to be described, its many alternative, correction and modification will be apparent to those skilled in the art.All this kind alternative, correction and variation all drop in spirit of the present invention and the scope.

Claims (136)

1. following formula: compound:
Or its pharmacy acceptable salt or solvate, wherein:
Expression N or N one of among a, b, c and the d +O -, and all the other a, b, c and d group are represented carbon, wherein each carbon has the R that is combined on this carbon 1Or R 2Group; Or
Each a, b, c and d are carbon, and wherein each carbon has the R that is combined on this carbon 1Or R 2Group;
Dotted line (---) the optional key of expression;
When this optional key (to C11) when not existing, X represents N or CH, and when this key (to C11) of choosing wantonly when existing, X represents C;
When having optional key between carbon atom 5 (meaning is C-5) and the carbon atom 6 (meaning is C-6), then have only an A substituting group to be combined on the C-5, and have only a B substituting group to be combined on the C-6, and A or B are not H;
When not having optional key between carbon atom 5 and the carbon atom 6, then there are two A substituting groups to be combined on the C-5, wherein each A substituting group is independent the selection, and there are two B substituting groups to be combined on the C-6, wherein each B substituting group is independent the selection, and wherein have at least in two A substituting groups to have at least to be a H in one or two B substituting group, have at least one not to be H in one or two B substituting group and wherein have at least in two A substituting groups;
A and B are independently selected from:
(1)-H；
(2)-R 9；
(3)-R 9-C(O)-R 9；
(4)-R 9-CO 2-R 9a；
(5)-(CH 2) pR 26；
(6)-C (O) N (R 9) 2, each R wherein 9Identical or different;
(7)-C(O)NHR 9；
(8)-C(O)NH-CH 2-C(O)-NH 2；
(9)-C(O)NHR 26；
(10)-(CH 2) pC(R 9)-O-R 9a；
(11)-(CH 2) P-1CH (R 9) 2, its condition is that p is not 0, and each R wherein 9Identical or different;
(12)-(CH 2) pC(O)R 9；
(13)-(CH 2) pC(O)R 27a；
(14)-(CH 2) pC (O) N (R 9) 2, each R wherein 9Identical or different;
(15)-(CH 2) pC(O)NH(R 9)；
(16)-(CH 2) pC (O) N (R 26) 2, each R wherein 26Identical or different;
(17)-(CH 2) pN(R 9)-R 9a；
(18)-(CH 2) pN (R 26) 2, R wherein 26Identical or different;
(19)-(CH 2) pNHC(O)R 50；
(20)-(CH 2) pNHC(O) 2R 50；
(21)-(CH 2) pN (C (O) R 27a) 2, each R wherein 27aIdentical or different;
(22)-(CH 2) pNR 51C(O)R 27；
(23)-(CH 2) pNR 51C (O) R 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(24)-(CH 2) pNR 51C(O)NR 27；
(25)-(CH 2) pNR 51C (O) NR 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(26)-(CH 2) pNR 51C (O) N (R 27a) 2, each R wherein 27aIdentical or different;
(27)-(CH 2) pNHSO 2N (R 51) 2, each R wherein 51Identical or different;
(28)-(CH 2) pNHCO 2R 50；
(29)-(CH 2) pNC(O)NHR 51；
(30)-(CH 2) pCO 2R 51；
(31)-NHR 9；
(32)
Figure A038047200004C1
R wherein 30With R 31Identical or different, and each p is independent the selection; Its condition is to each
Figure A038047200004C2
Group is worked as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl and aralkyl;
(33)
R wherein 30, R 31, R 32And R 33Identical or different; Its condition is to work as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl and aralkyl; And its condition is to work as R 32Or R 33In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 32Or R 33Be selected from: H, alkyl, aryl and aralkyl;
(34)-thiazolinyl-CO 2R 9a
(35)-thiazolinyl-C (O) R 9a
(36)-thiazolinyl-CO 2R 51
(37)-thiazolinyl-C (O)-R 27a
(38) (CH 2) p-thiazolinyl-CO 2-R 51
(39)-(CH 2) pC=NOR 51And
(40)-(CH 2) p-phthalic imidine;
P is 0,1,2,3 or 4;
Each R 1With R 2Be independently selected from:
(1)H；
(2) halogen;
(3)-CF 3；
(4)-OR 10；
(5)-COR 10；
(6)-SR 10；
(7)-S (O) tR 15, wherein t is 0,1 or 2;
(8)-N(R 10) 2；
(9)-NO 2；
(10)-OC(O)R 10；
(11)-CO 2R 10；
(12)-OCO 2R 15；
(13)-CN；
(14)-NR 10COOR 15；
(15)-SR 15C(O)OR 15；
(16)-SR 15N (R 13) 2, its condition is-SR 15N (R 13) 2In R 15Be not-CH 2, and each R wherein 13Be independently selected from: H and-C (O) OR 15
(17) benzotriazole-1-base oxygen base;
(18) tetrazolium-5-base sulfenyl;
(19) substituted tetrazolium-5-base sulfenyl;
(20) alkynyl;
(21) thiazolinyl; And
(22) alkyl, this alkyl or alkenyl optional by halogen ,-OR 10Or-CO 2R 10Replace;
R 3With R 4Identical or different, and each represents H and R independently 1With R 2Any substituting group;
R 5, R 6, R 7And R 7aEach is expression independently: H ,-CF 3,-COR 10, alkyl or aryl, this alkyl or aryl is chosen quilt-S (O) wantonly tR 15,-NR 10COOR 15,-C (O) R 10Or-CO 2R 10Replace, or R 5With R 6Together expression=O or=S;
R 8Be selected from:
H,
Figure A038047200006C1
With
R 9Be selected from:
(1) unsubstituted heteroaryl;
(2) substituted heteroaryl;
(3) alkoxy aryl;
(4) substituted alkoxy aryl;
(5) Heterocyclylalkyl;
(6) substituted Heterocyclylalkyl;
(7) Heterocyclylalkyl alkyl;
(8) substituted Heterocyclylalkyl alkyl;
(9) unsubstituted heteroaralkyl;
(10) substituted heteroaralkyl;
(11) unsubstituted heteroaryl thiazolinyl;
(12) substituted heteroaryl thiazolinyl;
(13) unsubstituted heteroaryl alkynyl; And
(14) substituted heteroaryl alkynyl;
This substituted R wherein 9Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CO 2R 14；
(3)-CH 2OR 14；
(4) halogen;
(5) alkyl;
(6) amino;
(7) trityl;
(8) Heterocyclylalkyl;
(9) cycloalkyl;
(10) aralkyl;
(11) heteroaryl;
(12) heteroaralkyl, and
(13)
R wherein 14Be independently selected from: H; Alkyl; Aryl, aralkyl, heteroaryl and heteroaralkyl;
R 9aBe selected from: alkyl and aralkyl;
R 9bBe selected from:
(1)-C(O)R 9a；
(2)-SO 2R 9a；
(3)-C(O)NHR 9a；
(4)-C (O) OR 9aAnd
(5)-C(O)N(R 9c) 2；
Each R 9cBe independently selected from: H, alkyl and aralkyl;
R 10Be selected from: H; Alkyl; Aryl and aralkyl;
R 11Be selected from:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) Heterocyclylalkyl;
(10) substituted Heterocyclylalkyl;
(11) unsubstituted thiazolinyl;
(12)-N (alkyl) 2, wherein each alkyl is independent the selection;
(13) unsubstituted aralkyl; And
(14) substituted aralkyl;
This substituted alkyl R wherein 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3)-CN; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3) alkyl; And
Wherein this substituted aryl, substituted heteroaryl reach this substituted aralkyl R 11The aryl moiety of group is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen;
(3) alkyl;
(4)-CF 3；
(5)-CN; And
(6) alkoxyl group;
R 11aBe selected from:
(1)H；
(2)OH；
(3) alkyl;
(4) substituted alkyl;
(5) aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) Heterocyclylalkyl;
(12) substituted Heterocyclylalkyl;
(13)-OR 9a；
(14) unsubstituted aralkyl;
(15) substituted aralkyl;
(16) unsubstituted thiazolinyl;
(17) unsubstituted aryl-acyl; And
(18) unsubstituted heteroaralkyl;
This substituted alkyl R wherein 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) cycloalkyl;
(6) Heterocyclylalkyl;
(7) aralkyl;
(8) heteroaralkyl; And
(9) assorted thiazolinyl; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl; And
(11) assorted thiazolinyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11aThe aryl moiety of group has one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl;
(11) assorted thiazolinyl;
(12) aryloxy; And
(13) alkoxyl group;
R 12Be selected from: H, alkyl, piperidine ring V, cycloalkyl reach-alkyl-(piperidine ring V) (wherein this piperidine ring V is as mentioned below);
R 15Be selected from: alkyl and aryl;
R 21, R 22And R 46Be independently selected from:
(1)-H；
(2) alkyl;
(3) unsubstituted aryl;
(4) be substituted aryl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(5) unsubstituted cycloalkyl;
(6) be substituted cycloalkyl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(7) following formula heteroaryl:
With
(8) following formula Heterocyclylalkyl:
Figure A038047200011C3
R wherein 44Be selected from:
(a)-H；
(b) alkyl;
(c) alkyl carbonyl;
(d) carbalkoxy;
(e) haloalkyl; And
(f)-C(O)NH(R 51)；
(9)-NH 2, its condition is R 21, R 22And R 46Have only one to can be-NH in the group 2, and its condition is to work as R 21, R 22And R 46In one of be-NH 2The time, then all the other groups are not-OH;
(10)-and OH, its condition is R 21, R 22And R 46Have only one to can be-OH in the group, and its condition is to work as R 21, R 22And R 46In one of be-during OH, then all the other groups are not-NH 2And
(11) alkyl that is replaced by one or more substituting group, described substituting group is selected from :-OH and-NH 2, its condition is to have only one-OH or one-NH on substituted carbon 2Group;
(12) alkoxyl group; Or
(13) R 21With R 22Form cyclic rings together with their institute's bonded carbon, described ring is selected from:
(a) unsubstituted cycloalkyl;
(b) cycloalkyl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(c) unsubstituted cycloalkenyl group;
(d) cycloalkenyl group that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CF 3And OH;
(e) Heterocyclylalkyl;
(f) unsubstituted aryl;
(g) aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CN ,-CF 3, OH and alkoxyl group; And
(i) heteroaryl, described heteroaryl is selected from:
Figure A038047200012C1
With
R 26Be selected from:
(1)-H；
(2) alkyl;
(3) alkoxyl group;
(4)-CH 2-CN；
(5)R 9；
(6)-CH 2CO 2H；
(7)-C (O) alkyl; And
(8) CH 2CO 2Alkyl;
R 27Be selected from:
(1)-H；
(2)-OH；
(3) alkyl; And
(4) alkoxyl group;
R 27aBe selected from:
(1) alkyl; With
(2) alkoxyl group;
R 30, R 31, R 32And R 33Be independently selected from:
(1)-H；
(2)-OH；
(3)＝O；
(4) alkyl;
(5) aryl;
(6) aralkyl;
(7)-OR 9a；
(8)-NH 2；
(9)-NHR 9a；
(10)-N (R 9a) 2, each R wherein 9aBe independent the selection;
(11)-N 3；
(12)-NHR 9bAnd
(13)-N(R 9a)R 9b；
R 50Be selected from:
(1) alkyl;
(2) unsubstituted heteroaryl;
(3) substituted heteroaryl; And
(4) amino;
Wherein at this substituted R 50Substituting group on the group is independently selected from: alkyl; Halogen; And-OH;
R 51Be selected from: H and alkyl; And
Its condition is:
(1) in substituted Heterocyclylalkyl part, the ring carbon atom adjacent with ring hetero atom do not replaced by heteroatoms or halogen atom; And
(2) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not exceeded a heteroatoms and replaces; And
(3) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not replaced by heteroatoms and halogen atom; And
(4) the ring carbon in being substituted cycloalkyl moiety is not exceeded a heteroatoms replacement; And
(5) carbon atom in being substituted moieties is not exceeded a heteroatoms replacement; And
(6) the same carbon atom in being substituted moieties had not only replaced by heteroatoms but also by halogen atom; And
(7) when A and B are independently selected from substituting group (1) to (31) and (34) to (39), R then 8Be not H; And
(8) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (2.0), R then 11Be selected from substituting group (11) to (14); And
(9) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (3.0), R then 11Be selected from substituting group (11) to (14); And
(10) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (4.0), then: (a) R 11aBe selected from substituting group (13) to (18), and R 12Definition, or (b) R as mentioned 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (c) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V); And
(11) be selected from substituting group (1) to (31) and (34) to (39) as A and B, and R 8During for (5.0), R then 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(12) in A and B, have at least one to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33When being selected from substituting group (1) to (6), R then 8Be selected from:
(a) (2.0), wherein R 11Be selected from substituting group (11) to (14),
(b) (3.0), wherein R 11Be selected from substituting group (11) to (14),
(c) (4.0), wherein (i) R 11aBe selected from substituting group (13) to (18), and R 12Define about formula 1.0 as mentioned, or (ii) R 11aBe selected from substituting group (1) extremely
And R (12), 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (iii) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), and
(d) (5.0), wherein R 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(13) in A and B, have at least one to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-NH 2, and R 8During for (2.0), R then 8Be not
Figure A038047200014C1
With
(14) in A and B, have at least one to be substituting group (32) or (33) (being preferably (32)), and R 30To R 33In have at least one to be-N 3, and R 8During for (2.0), R then 8Be not
2. according to the compound of claim 1, wherein said compound has following structure:
Wherein:
X=N; And
A is H, and has optional key between C-5 and C-6.
3. according to the compound of claim 1, R wherein 1To R 4Respectively be independently selected from H or halogen.
4. according to the compound of claim 1, R wherein 5, R 6, R 7And R 7aBe H.
5. according to the compound of claim 1, wherein a is N, and all the other b, c and d substituting group are carbon.
6. according to the compound of claim 1, wherein a, b, c and d are carbon.
7. according to the compound of claim 1, wherein between C-5 and C-6, there is optional key.
8. according to the compound of claim 1, wherein between C-5 and C-6, there is not optional key.
9. according to the compound of claim 1, R wherein 8Be group 2.0 or 4.0.
10. according to the compound of claim 1, wherein have two keys between C-5 and C-6, A is H, and B is R 9
11. according to the compound of claim 1, wherein:
(1) R 11Be selected from: alkyl, cycloalkyl and substituted cycloalkyl, wherein substituting group is selected from: halogen, alkyl and amino;
(2) R 11aBe selected from: alkyl, unsubstituted aryl, substituted aryl, cycloalkyl or substituted cycloalkyl wherein are selected from this substituting group that is substituted on the group: halogen ,-CN or CF 3
(3) R 12, R 21And R 22Be H; And
(4) R 46Be selected from: unsubstituted aryl,
With
Substituted aryl, wherein substituting group is selected from: alkyl, alkyl carbonyl and haloalkyl, and R wherein 44Be selected from: H or-C (O) NH 2
12. according to the compound of claim 1, wherein A is H, have two keys between C-5 and C-6, and B is following group:
And in this B group:
(1)-(CH 2) pThe p of-part is 0;
(2) with the p of lower section
Figure A038047200016C3
Be 1 to 3;
(3) for the lower section, when p is 1
Then
(a) R 30For-OH, and R 31Be H; Or
(b) R 30For-NH 2, and R 31Be H; Or
(c) R 30Be selected from:
(i)-OR 9a, R wherein 9aBe C 1To C 3Alkyl;
(ii)-N 3；
(iii)-NHR 9bAnd
(iv)-NR 9aR 9bAnd
R 31Be selected from: H and alkyl;
(4) for the lower section, when p is 2 or 3
Then:
(a) to one-CR 30R 31-part
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl;
(2)-N 3；
(3)-NHR 9bAnd
(4)-NR 9aR 9bAnd
R 31Be selected from: H and alkyl; With
(b) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; And
(5) R 9Be unsubstituted heteroaryl or substituted heteroaryl, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part.
13. according to the compound of claim 12, wherein B is following group:
Wherein in this B group:
(1)-(CH 2) pThe p of-part is 0;
(2) with the p of lower section
Figure A038047200018C2
Be 1;
(3)
(a) R 30For-OH, and R 31Be H; Or
(b) R 30For-NH 2, and R 31Be H; Or
(c) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl;
(2)-N 3；
(3)-NHR 9bAnd
(4)-NR 9aR 9bAnd
R 31Be selected from: H and alkyl; And
(4) R 9Be unsubstituted heteroaryl or substituted heteroaryl, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part.
14. according to the compound of claim 13, wherein R 9Be substituted imidazolyl.
15. according to the compound of claim 14, wherein this substituted imidazolyl is:
Figure A038047200019C1
16. according to the compound of claim 15, wherein: X is N.
17. according to the compound of claim 1, wherein A is H, have two keys between C-5 and C-6, and B is following group:
Wherein in this B group:
(1)-(CH 2) pThe p of-part is 0;
(2) with the p of lower section
Be 1;
(3) R 30Be selected from :-OH and-NH 2, and R 31Be C 1-C 2Alkyl; And
(4) R 9Be substituted imidazolyl, wherein substituting group is an alkyl, and its condition is that this imidazolyl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part.
18. according to the compound of claim 17, wherein this substituted imidazolyl is:
19. according to the compound of claim 18, wherein: X is N.
20. following formula: compound:
Figure A038047200020C1
Or its pharmacy acceptable salt or solvate, wherein:
(A) expression N or N one of among a, b, c and the d +O -, and all the other a, b, c and d group are represented CR 1, each R on each carbon wherein 1Group is identical or different; Or
(B) each a, b, c and d group are represented CR 1, each R on each carbon wherein 1Group is identical or different;
(C) the optional key of dotted line (---) expression;
(D) when this optional key (to C11) when not existing, X represents N or CH, and when this key (to C11) of choosing wantonly when existing, X represents C;
(E) B is following group:
And in this B group:
(1)-(CH 2) pThe p of-part is 0;
(2) with the p of lower section
Figure A038047200021C1
Be 1 to 3, be preferably 1 to 2, most preferably be 1;
(3) for the lower section, when p is 1
Figure A038047200021C2
Then
(a) R 30For-OH, and R 31Be H; Or
(b) R 30For-NH 2, and R 31Be H; Or
(c) R 30Be selected from:
(i)-OR 9a, R wherein 9aBe C 1To C 3Alkyl;
(ii)-N 3；
(iii)-NHR 9b, R wherein 9bAnd
(iv)-N (R 9a) R 9b, R wherein 9aWith R 9bAnd
R 31Be selected from: H and alkyl;
(4) for the lower section, when p is 2 or 3
Then:
(a) to one-CR 30R 31-part
(i) R 30For-OH, and R 31Be H; Or
(ii) R 30For-NH 2, and R 31Be H; Or
(iii) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C 1To C 3Alkyl;
(2)-N 3；
(3)-NHR 9bAnd
(4)-N (R 9a) R 9b, R wherein 9aWith R 9bAnd
R 31Be selected from: H and alkyl; With
(b) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; And
(5) R 9Be unsubstituted heteroaryl or substituted heteroaryl, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(F) R 1Be selected from:
(1)H；
(2) halogen;
(3)-CF 3；
(4)-OR 10；
(5)COR 10；
(6)-SR 10；
(7)-S(O) tR 15；
(8)-N(R 10) 2；
(9)-NO 2；
(10)-OC(O)R 10；
(11)CO 2R 10；
(12)-OCO 2R 15；
(13)-CN；
(14)-NR 10COOR 15；
(15)-SR 15C(O)OR 15；
(16)-SR 15N (R 13) 2, each R wherein 13Be independently selected from: H and-C (O) OR 15, and its condition is-SR 15N (R 13) 2In R 15Be not-CH 2
(17) benzotriazole-1-base oxygen base;
(18) tetrazolium-5-base sulfenyl;
(19) substituted tetrazolium-5-base sulfenyl;
(20) alkynyl;
(21) thiazolinyl;
(22) alkyl;
(23) alkyl that is replaced by one or more substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10
(24) thiazolinyl that is replaced by one or more substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10(G) each R 3ABe independently selected from:
(1) halogen;
(2)-CF 3；
(3)-OR 10；
(4)COR 10；
(5)-SR 10；
(6)-S(O) tR 15；
(7)-N(R 10) 2；
(8)-NO 2；
(9)-OC(O)R 10；
(10)CO 2R 10；
(11)-OCO 2R 15；
(12)-CN；
(13)-NR 10COOR 15；
(14)-SR 15C(O)OR 15；
(15)-SR 15N (R 13) 2, each R wherein 13Be independently selected from: H and-C (O) OR 15, and its condition is-SR 15N (R 13) 2In R 15Be not-CH 2
(16) benzotriazole-1-base oxygen base;
(17) tetrazolium-5-base sulfenyl;
(18) substituted tetrazolium-5-base sulfenyl;
(19) alkynyl;
(20) thiazolinyl;
(21) alkyl;
(22) alkyl that is replaced by one or more substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10And
(23) thiazolinyl that is replaced by one or more substituting group, described substituting group is independently selected from: halogen ,-OR 10And-CO 2R 10
(H) m is 0,1 or 2;
(I) t is 0,1 or 2;
(J) R 5, R 6, R 7And R 7aRespectively be independently selected from:
(1)H；
(2)-CF 3；
(3)-COR 10；
(4) alkyl;
(5) unsubstituted aryl;
(6) alkyl that is replaced by one or more group, this group is selected from :-S (O) tR 15,-NR 10COOR 15,-C (O) R 10And-CO 2R 10And
(7) aryl that is replaced by one or more (for example 1,2 or 3) group, this group is selected from :-S (O) tR 15,-NR 10COOR 15,-C (O) R 10And-CO 2R 10, or
(K) R 5With R 6Together expression=O or=S;
(L) R 8Be selected from:
H,
Figure A038047200024C1
With
(M) R 9aBe selected from: alkyl and aralkyl;
(N) R 9bBe selected from:
(1)-C(O)R 9a；
(2)-SO 2R 9a；
(3)-C(O)NHR 9a；
(4)-C (O) OR 9aAnd
(5)-C(O)N(R 9c) 2；
(O) each R 9cBe independently selected from: H, alkyl and aralkyl;
(P) R 10Be selected from: H; Alkyl; Aryl and aralkyl;
(Q) R 11Be selected from:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) Heterocyclylalkyl; With
(10) substituted Heterocyclylalkyl;
(11) unsubstituted thiazolinyl;
(12)-N (alkyl) 2, wherein each alkyl is independent the selection;
(13) unsubstituted aralkyl; And
(14) substituted aralkyl;
This substituted alkyl R wherein 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3)-CN; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3) alkyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11The aryl moiety of group is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen;
(3) alkyl;
(4)-CF 3；
(5)-CN; And
(6) alkoxyl group;
(R) R 11aBe selected from:
(1)H；
(2)OH；
(3) alkyl;
(4) substituted alkyl;
(5) unsubstituted aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) Heterocyclylalkyl;
(12) substituted Heterocyclylalkyl;
(13)-OR 9a；
(14) unsubstituted aralkyl;
(15) substituted aralkyl;
(16) unsubstituted thiazolinyl;
(17) unsubstituted aryl-acyl; And
(18) unsubstituted heteroaralkyl; And
This substituted alkyl R wherein 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) cycloalkyl;
(6) Heterocyclylalkyl;
(7) aralkyl;
(8) heteroaralkyl; And
(9) assorted thiazolinyl; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl, and
(11) assorted thiazolinyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11aThe aryl moiety of group has one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl;
(11) assorted thiazolinyl;
(12) aryloxy; And
(13) alkoxyl group;
(S) R 12Be selected from: H, alkyl, piperidine ring V, cycloalkyl reach-alkyl-(piperidine ring V) (wherein this piperidine ring V is as mentioned below);
(T) R 15Be selected from: alkyl and aryl;
(U) R 21, R 22And R 46Be independently selected from:
(1)H；
(2) alkyl;
(3) unsubstituted aryl;
(4) the substituted aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(5) unsubstituted cycloalkyl;
(6) be substituted cycloalkyl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen ,-CF 3Or OH;
(7) following formula heteroaryl
Figure A038047200028C1
Or
(8) piperidine ring V:
Figure A038047200028C3
R wherein 44Be selected from:
(a)H；
(b) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(c) alkyl carbonyl;
(d) carbalkoxy;
(e) haloalkyl;
(f)-C (O) NH (R 51); And
(9)-NH 2, its condition is R 21, R 22And R 46In have only one to can be-NH 2, and its condition is to work as R 21, R 22And R 46In one of be-NH 2The time, then all the other groups are not-OH;
(10)-and OH, its condition is R 21, R 22And R 46In have only one to can be-OH, and its condition is to work as R 21, R 22And R 46In one of be-during OH, then all the other groups are not-NH 2
(11) alkyl that is replaced by one or more substituting group, described substituting group is selected from :-OH and-NH 2, and its condition is to have only one-OH or one-NH on substituted carbon 2Group; And
(12) alkoxyl group; Or
(13) R 21With R 22Form cyclic rings together with their institute's bonded carbon, described ring is selected from:
(a) unsubstituted cycloalkyl;
(b) cycloalkyl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(c) unsubstituted cycloalkenyl group;
(d) cycloalkenyl group that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(e) Heterocyclylalkyl;
(f) unsubstituted aryl;
(g) aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CN ,-CF 3, OH and alkoxyl group; And
(i) heteroaryl, described heteroaryl is selected from:
With
Figure A038047200029C2
(V) R 51Be selected from: H and alkyl; And
(W) its condition is:
(1) in substituted Heterocyclylalkyl part, the ring carbon atom adjacent with ring hetero atom do not replaced by heteroatoms or halogen atom; And
(2) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not exceeded a heteroatoms and replaces; And
(3) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not replaced by heteroatoms and halogen atom; And
(4) the ring carbon in being substituted cycloalkyl moiety is not exceeded a heteroatoms replacement; And
(5) carbon atom in being substituted moieties is not exceeded a heteroatoms replacement; And
(6) the same carbon atom in being substituted moieties had not only replaced by heteroatoms but also by halogen atom; And
(7) work as R 30To R 33When being selected from substituting group (1) to (6), R then 8Be selected from:
(a) (2.0), wherein R 11Be selected from substituting group (11) to (14),
(b) (3.0), wherein R 11Be selected from substituting group (11) to (14),
(c) (4.0), wherein (i) R 11aBe selected from substituting group (13) to (18), and R 12Definition, or (ii) R as mentioned 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (iii) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), and
(d) (5.0), wherein R 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(13) work as R 30To R 33In have at least one to be-NH 2, and R 8During for (2.0), R then 8Be not
With
(14) work as R 30To R 33In have at least one to be-N 3, and R 8During for (2.0), R then 8Be not
21. according to the compound of claim 20, wherein:
(1) a is N;
(2) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is a halogen, and all the other two R 1Substituting group is a hydrogen;
(3) m is 1, and R 3ABe halogen, or m is 2, and each R 3AIdentical or different halogen;
(4) R 5, R 6, R 7And R 7aBe H; And
(5) X is N or CH.
22., wherein between C-5 and C-6, have optional key according to the compound of claim 21.
23. according to the compound of claim 21, wherein: X is N.
24., wherein between C-5 and C-6, have optional key according to the compound of claim 23.
25. according to the compound of claim 24, wherein R 9Be substituted imidazolyl.
26. according to the compound of claim 25, wherein this substituted imidazolyl is:
27. according to the compound of claim 26, wherein m is 1, and R 3ABe halogen.
28. according to the compound of claim 27, wherein this halogen is C1.
29. according to the compound of claim 28, wherein this C1 is combined on the C-8.
30. according to the compound of claim 29, wherein b, c and d are CR 1Group, wherein all these R 1Substituting group is H.
31. according to claim 30 compound, R wherein 8Be 2.0.
32. according to the compound of claim 31, wherein R 11Be alkyl.
33. according to the compound of claim 32, wherein this alkyl is selected from: the sec.-propyl and the tertiary butyl.
34. according to the compound of claim 33, wherein this alkyl is a sec.-propyl.
35. following formula: compound:
Or its pharmacy acceptable salt or solvate, wherein:
(A) B is following group:
Wherein in this B group:
(1)-(CH 2) pThe p of-part is 0;
(2) with the p of lower section
Be 1;
(3)
(a) R 30For-OH, and R 31Be H; Or
(b) R 30For-NH 2, and R 31Be H; Or
(c) R 30Be selected from:
(1)-OR 9a, R wherein 9aBe C1 to C3 alkyl;
(2)-N 3；
(3)-NHR 9bAnd
(4)-NR 9aR 9bAnd
R 31Be selected from: H and alkyl; And
(4) R 9Be unsubstituted heteroaryl or substituted heteroaryl, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30Be selected from :-OH ,-NH 2,-OR 9a,-N 3And-NHR 9bThe time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(B) a is N;
(C) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen, and all the other two R 1Substituting group is a hydrogen;
(D) m is 1, and R 3ABe halogen, or m is 2, and each R 3AIdentical or different halogen;
(E) X is N or CH;
(F) R 5, R 6, R 7And R 7aBe H;
(G) R 8Be selected from:
H, With
(H) R 9aBe selected from: alkyl and aralkyl;
(I) R 9bBe selected from:
(1)-C(O)R 9a；
(2)-SO 2R 9a；
(3)-C(O)NHR 9a；
(4)-C (O) OR 9aAnd
(5)-C(O)N(R 9c) 2；
(J) each R 9cBe independently selected from: H, alkyl and aralkyl;
(K) R 11Be selected from:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) Heterocyclylalkyl; With
(10) substituted Heterocyclylalkyl;
(11) unsubstituted thiazolinyl;
(12)-N (alkyl) 2, wherein each alkyl is independent the selection;
(13) unsubstituted aralkyl; And
(14) substituted aralkyl;
This substituted alkyl R wherein 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3)-CN; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3) alkyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11The aryl moiety of group is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen;
(3) alkyl;
(4)-CF 3；
(5)-CN; And
(6) alkoxyl group;
(L) R 11aBe selected from:
(1)H；
(2)OH；
(3) alkyl;
(4) substituted alkyl;
(5) unsubstituted aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) Heterocyclylalkyl;
(12) substituted Heterocyclylalkyl;
(13)-OR 9a；
(14) unsubstituted aralkyl;
(15) substituted aralkyl;
(16) unsubstituted thiazolinyl;
(17) unsubstituted aryl-acyl; And
(18) unsubstituted heteroaralkyl; And
This substituted alkyl R wherein 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) cycloalkyl;
(6) Heterocyclylalkyl;
(7) aralkyl;
(8) heteroaralkyl; And
(9) assorted thiazolinyl; And wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl, and
(11) assorted thiazolinyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11aThe aryl moiety of group has one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl;
(11) assorted thiazolinyl;
(12) aryloxy; And
(13) alkoxyl group;
(M) R 12Be selected from: H, alkyl, piperidine ring V, cycloalkyl reach-alkyl-(piperidine ring V) (wherein this piperidine ring V is as mentioned below);
(N) R 21, R 22And R 26Be independently selected from:
(1)H；
(2) alkyl;
(3) unsubstituted aryl;
(4) be substituted aryl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(5) unsubstituted cycloalkyl;
(6) be substituted cycloalkyl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen ,-CF 3Or OH;
(7) following formula heteroaryl
Or
Figure A038047200037C2
(8) piperidine ring V:
Figure A038047200037C3
R wherein 44Be selected from:
(a)H；
(b) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(c) alkyl carbonyl;
(d) carbalkoxy;
(e) haloalkyl;
(f)-C (O) NH (R 51); And
(9)-NH 2, its condition is R 21, R 22And R 46In have only one to can be-NH 2, and its condition is to work as R 21, R 22And R 46In one of be-NH 2The time, then all the other groups are not-OH;
(10)-and OH, its condition is R 21, R 22And R 46In have only one to can be-OH, and its condition is to work as R 21, R 22And R 46In one of be-during OH, then all the other groups are not-NH 2
(11) alkyl that is replaced by one or more substituting group, described substituting group is selected from :-OH and-NH 2, and its condition is to have only one-OH or one-NH on substituted carbon 2Group; And
(12) alkoxyl group; Or
(13) R 21With R 22Form cyclic rings together with their institute's bonded carbon, described ring is selected from:
(a) unsubstituted cycloalkyl;
(b) cycloalkyl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(c) unsubstituted cycloalkenyl group;
(d) cycloalkenyl group that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(e) Heterocyclylalkyl;
(f) unsubstituted aryl;
(g) aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CN ,-CF 3, OH and alkoxyl group; And
(i) heteroaryl, described heteroaryl is selected from:
With
Figure A038047200038C2
(O) R 51Be selected from: H and alkyl; And
(P) its condition is:
(1) in substituted Heterocyclylalkyl part, the ring carbon atom adjacent with ring hetero atom do not replaced by heteroatoms or halogen atom; And
(2) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not exceeded a heteroatoms and replaces; And
(3) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not replaced by heteroatoms and halogen atom; And
(4) the ring carbon in being substituted cycloalkyl moiety is not exceeded a heteroatoms replacement; And
(5) carbon atom in being substituted moieties is not exceeded a heteroatoms replacement; And
(6) the same carbon atom in being substituted moieties had not only replaced by heteroatoms but also by halogen atom; And
(7) work as R 30To R 33When being selected from substituting group (1) to (6), then R8 is selected from:
(a) (2.0), wherein R 11Be selected from substituting group (11) to (14),
(b) (3.0), wherein R 11Be selected from substituting group (11) to (14),
(c) (4.0), wherein (i) R 11aBe selected from substituting group (13) to (18), and R 12
Definition, or (ii) R as mentioned 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (iii) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), and
(d) (5.0), wherein R 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(13) work as R 30To R 33In have at least one to be-NH 2, and R 8During for (2.0), R then 8Be not
With
(14) work as R 30To R 33In have at least one to be-N 3, and R 8During for (2.0), R then 8Be not
36. according to the compound of claim 35, wherein R 30Be selected from-OR 9a,-NHR 9bAnd-NR 9aR 9b
37. according to the compound of claim 35, wherein: X is N.
38. according to the compound of claim 37, wherein R 9Be substituted imidazolyl.
39. according to the compound of claim 38, wherein R 30Be selected from-OR 9a,-NHR 9bAnd-NR 9aR 9b
40. according to the compound of claim 38, wherein this substituted imidazolyl is:
Figure A038047200040C1
41. according to the compound of claim 40, wherein m is 1, and R 3ABe halogen.
42. according to the compound of claim 41, wherein this halogen is C1.
43. according to the compound of claim 42, wherein this C1 is combined on the C-8.
44. according to the compound of claim 42, wherein b, c and d are CR 1Group, wherein all these R 1Substituting group is H.
45. according to the compound of claim 44, wherein R 30Be selected from-OR 9a,-NHR 9bAnd-NR 9aR 9b
46. according to the compound of claim 44, wherein R 8Be 2.0.
47. according to the compound of claim 46, wherein R 30Be selected from-OR 9a,-NHR 9bAnd-NR 9aR 9b
48. according to the compound of claim 46, wherein R 11Be alkyl.
49. according to the compound of claim 48, wherein R 30Be selected from-OR 9a,-NHR 9bAnd-NR 9aR 9b
50. according to the compound of claim 48, wherein this alkyl is selected from: the sec.-propyl and the tertiary butyl.
51. according to the compound of claim 50, wherein this alkyl is a sec.-propyl.
52. according to the compound of claim 49, wherein R 30For-NHR 9b
53. according to the compound of claim 52, wherein R 9bFor-C (O) OR 9a, R wherein 9aBe alkyl.
54. according to the compound of claim 53, wherein R 31Be H.
55. according to the compound of claim 54, wherein R 11Be sec.-propyl.
56. according to the compound of claim 35, wherein R 30Be selected from-NH 2Or-NHR 9b, and R 31Be H.
57. according to the compound of claim 48, wherein R 30Be selected from-NH 2Or-NHR 9b, and R 31Be H.
58. according to the compound of claim 35, wherein R 30For-NH 2, and R 31Be H.
59. according to the compound of claim 48, wherein R 30For-NH 2, and R 31Be H.
60. according to the compound of claim 48, wherein R 30For-NHR 9b, and R 31Be H.
61. according to the compound of claim 42, described compound has following structure:
62. according to the compound of claim 35, wherein B is selected from:
Figure A038047200041C2
With
63. according to the compound of claim 35, wherein B is:
64. according to the compound of claim 35, wherein B is:
65. according to the compound of claim 35, wherein B is selected from:
With
66. according to the compound of claim 35, wherein B is:
67. according to the compound of claim 1 or 35, wherein R 8Be selected from:
Figure A038047200043C2
With
68. according to the compound of claim 1 or 35, wherein R 8Be selected from:
Figure A038047200044C2
With
Figure A038047200045C2
69. according to claim 1 or 35 compound, R wherein 8Be selected from:
Figure A038047200045C3
With
70. according to the compound of claim 1 or 35, wherein R 8Be selected from:
With
71. following formula: compound:
Figure A038047200046C4
Or its pharmacy acceptable salt or solvate, wherein:
(A) B is following group:
Figure A038047200047C1
(B) in this B group:
(1)-(CH 2) pThe p of-part is 0;
(2) with the p of lower section
Be 1 to 3;
(3) for the lower section, when p is for the moment
Figure A038047200047C3
R then 30Be selected from :-OH and-NH 2, and R 31Be alkyl;
(d) for the lower section, when p is 2 or 3
Figure A038047200047C4
Then: (1) is to one-CR 30R 31-part, R 30Be selected from :-OH and-NH 2, and R 31Be alkyl; With (2) to all the other-CR 30R 31-part, R 30With R 31Be hydrogen; And
(e) R 9Be unsubstituted heteroaryl or substituted heteroaryl, its condition is when this heteroaryl contains nitrogen in ring, then works as R 30For-OH or-NH 2The time, this heteroaryl is not combined in adjacent-CR via ring nitrogen 30R 31On-the part;
(C) a is N;
(D) b, c and d are CR 1Group, wherein all these R 1Substituting group is H, or a R 1Substituting group is halogen, and all the other two R 1Substituting group is a hydrogen;
(E) m is 1, and R 3ABe halogen, or m is 2, and each R 3AIdentical or different halogen;
(F) X is N or CH;
(G) R 5, R 6, R 7And R 7aBe H;
(H) R 8Be selected from:
H, With
(I) R 11Be selected from:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) Heterocyclylalkyl; With
(10) substituted Heterocyclylalkyl;
(11) unsubstituted thiazolinyl;
(12)-N (alkyl) 2, wherein each alkyl is independent the selection;
(13) unsubstituted aralkyl; And
(14) substituted aralkyl;
This substituted alkyl R wherein 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3)-CN; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3) alkyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11The aryl moiety of group is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen;
(3) alkyl;
(4)-CF 3；
(5)-CN; And
(6) alkoxyl group;
(J) R 11aBe selected from:
(1)H；
(2)OH；
(3) alkyl;
(4) substituted alkyl;
(5) unsubstituted aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) Heterocyclylalkyl;
(12) substituted Heterocyclylalkyl;
(13)-OR 9a；
(14) unsubstituted aralkyl;
(15) substituted aralkyl;
(16) unsubstituted thiazolinyl;
(17) unsubstituted aryl-acyl; And
(18) unsubstituted heteroaralkyl; And this substituted alkyl R wherein 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) cycloalkyl;
(6) Heterocyclylalkyl;
(7) aralkyl;
(8) heteroaralkyl; And
(9) assorted thiazolinyl; And
Wherein this substituted cycloalkyl and substituted Heterocyclylalkyl R 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl, and
(11) assorted thiazolinyl; And
Wherein this substituted aryl, substituted heteroaryl and this are substituted aralkyl R 11aThe aryl moiety of group has one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl;
(11) assorted thiazolinyl;
(12) aryloxy; And
(13) alkoxyl group;
(K) R 12Be selected from: H, alkyl, piperidine ring V, cycloalkyl reach-alkyl-(piperidine ring V) (wherein this piperidine ring V is as mentioned below);
(L) R 21, R 22And R 46Be independently selected from:
(1)H；
(2) alkyl;
(3) unsubstituted aryl;
(4) be substituted aryl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(5) unsubstituted cycloalkyl;
(6) be substituted cycloalkyl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen ,-CF 3Or OH;
(7) following formula heteroaryl,
Figure A038047200052C1
Or
(8) piperidine ring V:
Figure A038047200052C3
R wherein 44Be selected from:
(a)H；
(b) alkyl (for example methyl, ethyl, propyl group, butyl or the tertiary butyl);
(c) alkyl carbonyl;
(d) carbalkoxy;
(e) haloalkyl;
(f)-C (O) NH (R 51); And
(9)-NH 2, its condition is R 21, R 22And R 46In have only one to can be-NH 2, and its condition is to work as R 21, R 22And R 46In one of be-NH 2The time, then all the other groups are not-OH;
(10)-and OH, its condition is R 21, R 22And R 46In have only one to can be-OH, and its condition is to work as R 21, R 22And R 46In one of be-during OH, then all the other groups are not-NH 2
(11) alkyl that is replaced by one or more substituting group, described substituting group is selected from :-OH and-NH 2, and its condition is to have only one-OH or one-NH on substituted carbon 2Group; And
(12) alkoxyl group; Or
(13) R 21With R 22Form cyclic rings together with their institute's bonded carbon, described ring is selected from:
(a) unsubstituted cycloalkyl;
(b) cycloalkyl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(c) unsubstituted cycloalkenyl group;
(d) cycloalkenyl group that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(e) Heterocyclylalkyl;
(f) unsubstituted aryl;
(g) aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CN ,-CF 3, OH and alkoxyl group; And
(i) heteroaryl, described heteroaryl is selected from:
With
(M) R 51Be selected from: H and alkyl; And
(N) its condition is:
(1) in substituted Heterocyclylalkyl part, the ring carbon atom adjacent with ring hetero atom do not replaced by heteroatoms or halogen atom; And
(2) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not exceeded a heteroatoms and replaces; And
(3) in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not replaced by heteroatoms and halogen atom; And
(4) the ring carbon in being substituted cycloalkyl moiety is not exceeded a heteroatoms replacement; And
(5) carbon atom in being substituted moieties is not exceeded a heteroatoms replacement; And
(6) the same carbon atom in being substituted moieties had not only replaced by heteroatoms but also by halogen atom; And
(7) work as R 30To R 33When being selected from substituting group (1) to (6), R then 8Be selected from:
(a) (2.0), wherein R 11Be selected from substituting group (11) to (14),
(b) (3.0), wherein R 11Be selected from substituting group (11) to (14),
(c) (4.0), wherein (i) R 11aBe selected from substituting group (13) to (18), and R 12Definition, or (ii) R as mentioned 11aBe selected from substituting group (1) to (12), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), or (iii) R 11aBe selected from substituting group (13) to (18), and R 12Be selected from: cycloalkyl, piperidine ring V and alkyl-(piperidine ring V), and
(d) (5.0), wherein R 21, R 22And R 46In have at least one be selected from substituting group (8) (g), (8) (h), (9), (10), (11), (12) and (13); And
(13) work as R 30To R 33In have at least one to be-NH 2, and R 8During for (2.0), R then 8Be not
With
(14) work as R 30To R 33In have at least one to be-N 3, and R 8During for (2.0), R then 8Be not
72. compound, described compound are selected from the end product compound of embodiment 506 to 1573,1579 to 1582,1588 to 1591,1593 to 3062 and 3157 to 3255.
73. compound, described compound are selected from the end product compound of embodiment 1574 to 1578,1583 to 1587.
74. according to the compound of claim 1, described compound is selected from the end product compound of embodiment 1592,3063 to 3156 and 3256 to 3267.
75. compound, described compound are selected from the end product compound of embodiment 3268 to 3280 and 3303 to 4618.
76. according to the compound of claim 1, described compound is selected from the end product compound of following examples, embodiment 3281 to 3302, and
3303??????3309??????3316??????3396??????3402??????3409
3304??????3310??????3317??????3397??????3403??????3410
3311??????3318????????????????3404??????3411
3312??????3319????????????????3405??????3412
3313??????3320????????????????3406??????3413
3314??????3321????????????????3407??????3414
3315??????????????????????????3408??????3415
3322??????3328??????3335??????3416??????3422??????3429
3323??????3329??????3336??????3417??????3423??????3430
3330??????3337????????????????3424??????3431
3331??????3338????????????????3425??????3432
3332??????3339????????????????3426??????3433
3333??????3340????????????????3427??????3434
3334??????3341????????????????3428??????3435
3342??????3348??????3355??????3436??????3442??????3449
3343??????3349??????3356??????3437??????3443??????3450
3350??????3357????????????????3444??????3451
3351??????3358????????????????3445??????3452
3352??????3359????????????????3446??????3453
3353??????3360????????????????3447??????3454
3354??????3361????????????????3448??????3455
3362??????3368??????3375??????3456??????3462??????3469
3363??????3369??????3376??????3457??????3463??????3470
3370??????3377????????????????3464??????3471
3371??????3378????????????????3465??????3472
3372??????3379????????????????3466??????3473
3373??????3380????????????????3467??????3474
3374??????3381????????????????3468??????3475
3386??????3391??????3476??????3482??????3489
3384??????3387??????3392??????3477??????3483??????3490
3385??????3388??????3393????????????????3484??????3491
3389??????3394????????????????3485??????3492
3390??????3395????????????????3486??????3493
3487??????3494
3488
3495??????3501??????3508??????3632??????3638??????3645
3496??????3502??????3509??????3633??????3639??????3646
3503??????3510????????????????3640??????3647
3504??????3511????????????????3641??????3648
3505??????3512????????????????3642??????3649
3506??????3513????????????????3643??????3650
3507??????3514????????????????3644??????3651
3515??????3521??????3527??????3652??????3658??????3665
3516??????3522??????3528??????3653??????3659??????3666
3523??????3529????????????????3660??????3667
3524??????3530????????????????3661??????3668
3525??????3531????????????????3662??????3669
3526??????3532????????????????3663??????3670
3664??????3671
3533??????3539??????3546??????3672??????3678??????3685
3534??????3540??????3547a?????3673??????3679??????3686
3541??????3547????????????????3680??????3687
3542??????3548????????????????3681??????3688
3543??????3549????????????????3682??????3689
3544??????3550????????????????3683??????3690
3545??????3551????????????????3684??????3691
3552??????3558??????3565??????3692??????3698??????3705
3553??????3559??????3566??????3693??????3699??????3706
3560??????3567????????????????3700??????3707
3561??????3568????????????????3701??????3708
3562??????3569????????????????3702??????3709
3563??????3570????????????????3703??????3710
3664??????3571????????????????3704??????3711
3572??????3578??????3585??????3712??????3718??????3725
3573??????3579??????3586??????3713??????3719??????3726
3580??????3587????????????????3720??????3727
3581??????3588????????????????3721??????3728
3582??????3589????????????????3722??????3729
3583??????3590????????????????3723??????3730
3584??????3591????????????????3724??????3731
3592??????3598??????3605??????3732??????3738??????3745
3593??????3599??????3606??????3733??????3739??????3746
3600??????3607????????????????3740??????3747
3601??????3608????????????????3741??????3748
3602??????3609????????????????3742??????3749
3603??????3610????????????????3743??????3750
3604??????3611????????????????3744??????3751
3612??????3618??????3625??????3752??????3758??????3765
3613??????3619??????3626??????3753??????3759??????3766
3620??????3627????????????????3760??????3767
3621??????3628????????????????3761??????3768
3622??????3629????????????????3762??????3769
3623??????3630????????????????3763??????3770
3624??????3631????????????????3764??????3771
3772??????3778??????3785??????3911??????3916??????3923
3773??????3779??????3786????????????????3917??????3924
3780??????3787????????????????3918??????3925
3781??????3788????????????????3919??????3926
3782??????3789????????????????3920??????3927
3783??????3790????????????????3921??????3928
3784??????3791????????????????3922??????3929
3792??????3798??????3805??????3930??????3935??????3941
3793??????3799??????3806????????????????3936??????3942
3800??????3807??????3932??????3937??????3943
3801??????3808??????3933??????3938??????3944
3802??????3809??????3934??????3940??????3945
3803??????3810
3804??????3811
3812??????3818???????3825???????3946???????3952???????3959
3813??????3819???????3826???????3947???????3953???????3960
3820???????3827??????????????????3954???????3961
3821???????3828??????????????????3955???????3962
3822???????3829??????????????????3956???????3963
3823???????3830??????????????????3957???????3964
3824???????3831??????????????????3958???????3965
3832??????3838???????3845???????3966???????3972???????3979
3833??????3839???????3846???????3967???????3973???????3980
3840???????3847??????????????????3974???????3981
3841???????3848??????????????????3975???????3982
3842???????3849??????????????????3976???????3983
3843???????3850??????????????????3977???????3984
3844???????3851??????????????????3978???????3985
3852??????3858???????3865???????3986???????3992???????3999
3853??????3859???????3866???????3987???????3993???????3400.1
3860???????3867??????????????????3994???????3401.1
3861???????3868??????????????????3995???????3402.1
3862???????3869??????????????????3996???????3403.1
3863???????3870??????????????????3997???????3404.1
3864???????3871??????????????????3998???????3405.1
3872??????3878???????3885???????3406.1?????3412.1?????3419.1
3873??????3879???????3886???????3407.1?????3413.1?????3420.1
3880???????3887??????????????????3414.1?????3421.1
3881???????3888??????????????????3415.1?????3422.1
3882???????3889??????????????????3416.1?????3423.1
3883???????3890??????????????????3417.1?????3424.1
3884???????3891??????????????????3418.1?????3425.1
3892??????3897???????3904???????3426.1?????3432.1?????3439.1
3898???????3905???????3427.1?????3433.1?????3440.1
3899???????3906??????????????????3434.1?????3441.1
3900???????3907??????????????????3435.1?????3442.1
3901???????3908??????????????????3436.1?????3443.1
3902???????3909??????????????????3437.1?????3444.1
3903???????3910??????????????????3438.1?????3445.1
3446.1????3452.1?????3459.1?????3586.1?????3592.1?????3599.1
3447.1????3453.1?????3460.1?????3587.1?????3593.1?????3600.1
3454.1?????3461.1????????????????3594.1?????3601.1
3455.1?????3462.1????????????????3595.1?????3602.1
3456.1?????3463.1????????????????3596.1?????3603.1
3457.1?????3464.1????????????????3597.1?????3604.1
3458.1?????3465.1????????????????3598.1?????3605.1
3466.1????3472.1?????3479.1?????3606.1?????3612.1?????3619.1
3467.1????3473.1?????3480.1?????3607.1?????3613.1?????3620.1
3474.1?????3481.1????????????????3614.1?????3621.1
3475.1?????3482.1????????????????3615.1?????3622.1
3476.1?????3483.1????????????????3616.1?????3623.1
3477.1?????3484.1????????????????3617.1?????3624.1
3478.1?????3485.1????????????????3618.1?????3625.1
3486.1??????3492.1??????3499.1??????3626.1??????3632.1??????3639.1
3487.1??????3493.1??????3500.1??????3627.1??????3633.1??????3640.1
3494.1??????3501.1??????????????????3634.1??????3641.1
3495.1??????3502.1??????????????????3635.1??????3642.1
3496.1??????3503.1??????????????????3636.1??????3643.1
3497.1??????3504.1??????????????????3637.1??????3644.1
3498.1??????3505.1??????????????????3638.1??????3645.1
3506.1??????3512.1??????3519.1??????3646.1??????3652.1??????3659.1
3507.1??????3513.1??????3520.1??????3647.1??????3653.1??????3660.1
3514.1??????3521.1??????????????????3654.1??????3661.1
3515.1??????3522.1??????????????????3655.1??????3662.1
3516.1??????3523.1??????????????????3656.1??????3663.1
3517.1??????3524.1??????????????????3657.1??????3664.1
3518.1??????3525.1??????????????????3658.1??????3665.1
3526.1??????3532.1??????3539.1??????3666.1??????3672.1??????3679.1
3527.1??????3533.1??????3540.1??????3667.1??????3673.1??????3680.1
3534.1??????3541.1??????????????????3674.1??????3681.1
3535.1??????3542.1??????????????????3675.1??????3682.1
3536.1??????3543.1??????????????????3676.1??????3683.1
3537.1??????3544.1??????????????????3677.1??????3684.1
3538.1??????3545.1??????????????????3678.1??????3685.1
3546.1??????3552.1??????3559.1??????3686.1??????3692.1??????3699.1
3547.1??????3553.1??????3560.1??????3687.1??????3693.1??????3700.1
3554.1??????3561.1??????????????????3694.1??????3701.1
3555.1??????3562.1??????????????????3695.1??????3702.1
3556.1??????3563.1??????????????????3696.1??????3703.1
3557.1??????3564.1??????????????????3697.1??????3704.1
3558.1??????3565.1??????????????????3698.1??????3705.1
3566.1??????3572.1??????3579.1??????3706.1??????3712.1??????3719.1
3567.1??????3573.1??????3580.1??????3707.1??????3713.1??????3720.1
3574.1??????3581.1??????????????????3714.1??????3721.1
3575.1??????3582.1??????????????????3715.1??????3722.1
3576.1??????3583.1??????????????????3716.1??????3723.1
3577.1??????3584.1??????????????????3717.1??????3724.1
3578.1??????3585.1??????????????????3718.1??????3725.1
3726.1??????3732.1??????3739.1??????3864.1??????3870.1??????3877.1
3727.1??????3733.1??????3740.1??????3865.1??????3871.1??????3878.1
3734.1??????3741.1??????????????????3872.1??????3879.1
3735.1??????3742.1??????????????????3873.1??????3880.1
3736.1??????3743.1??????????????????3874.1??????3881.1
3737.1??????3744.1??????????????????3875.1??????3882.1
3738.1??????3745.1??????????????????3876.1??????3883.1
3746.1??????3752.1??????3759.1??????3884.1??????3890.1??????3897.1
3747.1??????3753.1??????3760.1??????3885.1??????3891.1??????3898.1
3754.1??????3761.1??????????????????3892.1??????3899.1
3755.1??????3762.1??????????????????3893.1??????3900.1
3756.1??????3763.1??????????????????3894.1??????3901.1
3757.1??????3764.1??????????????????3895.1??????3902.1
3758.1??????3765.1??????????????????3896.1??????3903.1
3766.1??????3772.1??????3779.1??????3904.1??????3910.1??????3917.1
3767.1??????3773.1??????3780.1??????3905.1??????3911.1??????3918.1
3774.1??????3781.1??????????????????3912.1??????3919.1
3775.1??????3782.1??????????????????3913.1??????3920.1
3776.1??????3783.1??????????????????3914.1??????3921.1
3777.1??????3784.1??????????????????3915.1??????3922.1
3778.1??????3785.1??????????????????3916.1??????3923.1
3786.1??????3792.1??????3799.1??????3944.1??????3950.1??????3957.1
3787.1??????3793.1??????3800.1??????3945.1??????3951.1??????3958.1
3794.1??????3801.1??????????????????3952.1??????3959.1
3795.1??????3802.1??????????????????3953.1??????3960.1
3796.1??????3803.1??????????????????3954.1??????3961.1
3797.1??????3804.1??????????????????3955.1??????3962.1
3798.1??????3805.1??????????????????3956.1??????3963.1
3806.1??????3812.1??????3818.1??????3964.1??????3970.1??????3977.1
3807.1??????3813.1??????3819.1??????3965.1??????3971.1??????3978.1
3814.1??????3820.1??????????????????3972.1??????3979.1
3815.1??????3821.1??????????????????3973.1??????3980.1
3816.1??????3822.1??????????????????3974.1??????3981.1
3817.1??????3823.1??????????????????3975.1??????3982.1
3976.1??????3983.1
3824.1??????3830.1??????3837.1??????3984.1??????3990.1??????3997.1
3825.1??????3831.1??????3838.1??????3985.1??????3991.1??????3998.1
3832.1??????3839.1??????????????????3992.1??????3999.1
3833.1??????3840.1??????????????????3993.1??????4000
3834.1??????3841.1??????????????????3994.1??????4001
3835.1??????3842.1??????????????????3995.1??????4002
3836.1??????3843.1??????????????????3996.1??????4003
3844.1??????3850.1??????3857.1??????4004????????4010????????4017
3845.1??????3851.1??????3858.1??????4005????????4011????????4018
3852.1??????3859.1??????????????????4012????????4019
3853.1??????3860.1??????????????????4013????????4020
3854.1??????3861.1??????????????????4014????????4021
3855.1??????3862.1??????????????????4015????????4022
3856.1??????3863.1??????????????????4016????????4023
4024???????4030????????4037????????4164????????4170????????4177
4025???????4031????????4038????????4165????????4171????????4178
4032????????4039????????????????????4172????????4179
4033????????4040????????????????????4173????????4180
4034????????4041????????????????????4174????????4181
4035????????4042????????????????????4175????????4182
4036????????4043????????????????????4176????????4183
4044???????4050????????4057????????4184????????4190????????4197
4045???????4051????????4058????????4185????????4191????????4198
4052????????4059????????????????????4192????????4199
4053????????4060????????????????????4193????????4200
4054????????4061????????????????????4194????????4201
4055????????4062????????????????????4195????????4202
4056????????4063????????????????????4196????????4203
4064??????4070??????4077??????4204??????4210??????4217
4065??????4071??????4078??????4205??????4211??????4218
4072??????4079????????????????4212??????4219
4073??????4080????????????????4213??????4220
4074??????4081????????????????4214??????4221
4075??????4082????????????????4215??????4222
4076??????4083????????????????4216??????4223
4084??????4090??????4097??????4224??????4230??????4237
4085??????4091??????4098??????4225??????4231??????4238
4092??????4099????????????????4232??????4239
4093??????4100????????????????4233??????4240
4094??????4101????????????????4234??????4241
4095??????4102????????????????4235??????4242
4096??????4103????????????????4236??????4243
4104??????4110??????4117??????4244??????4250??????4257
4105??????4111??????4118??????4245??????4251??????4258
4112??????4119????????????????4252??????4259
4113??????4120????????????????4253??????4260
4114??????4121????????????????4254??????4261
4115??????4122????????????????4255??????4262
4116??????4123????????????????4256??????4263
4124??????4130??????4137??????4264??????4270??????4277
4125??????4131??????4138??????4265??????4271??????4278
4132??????4139????????????????4272??????4279
4133??????4140????????????????4273??????4280
4134??????4141????????????????4274??????4281
4135??????4142????????????????4275??????4282
4136??????4143????????????????4276??????4283
4144??????4150??????4157??????4284??????4290??????4297
4145??????4151??????4158??????4285??????4291??????4298
4152??????4159????????????????4292??????4299
4153??????4160????????????????4293??????4300
4154??????4161????????????????4294??????4301
4155??????4162????????????????4295??????4302
4156??????4163????????????????4296??????4303
4304??????4310??????4316??????4441??????4447??????4454??????4581
4305??????4311??????4317??????4442??????4448??????4455??????4582
4312??????4317a???????????????4449??????4456
4313??????4320????????????????4450??????4457
4314??????????????????????????4451??????4458
4315??????????????????????????4452??????4459
4453??????4460
4321??????4327??????4334?????4461???????4467??????4474??????4587
4322??????4328??????4335?????4462???????4468??????4475??????4588
4329??????4336????????????????4469??????4476??????4589
4330??????4337????????????????4470??????4477??????4590
4331??????4338????????????????4471??????4478??????4591
4332??????4339????????????????4472??????4479??????4592
4333??????4340????????????????4473??????4480??????4593
4341???????4347???????4354???????4481????4487???????4494???????4594
4342???????4348???????4355???????4482????4488???????4495???????4595
4349???????4356???????????????4489???????4496???????4596
4350???????4357???????????????4490???????4497???????4597
4351???????4358???????????????4491???????4498???????4598
4352???????4359???????????????4492???????4499???????4599
4353???????4360???????????????4493???????4500???????4600
4361???????4367???????4374???????4501????4507???????4514???????4601
4362???????4368???????4375???????4502????4508???????4515???????4602
4369???????4376???????????????4509???????4516
4370???????4377???????????????4510???????4517
4371???????4378???????????????4511???????4518
4372???????4379???????????????4512???????4519
4373???????4380???????????????4513???????4520
4381???????4387???????4394???????4521????4527???????4534???????4607
4382???????4388???????4395???????4522????4528???????4535???????4608
4389???????4396???????????????4529???????4536???????4609
4390???????4397???????????????4530???????4537???????4610
4391???????4398???????????????4531???????4538???????4611
4392???????4399???????????????4532???????4539???????4612
4393???????4400???????????????4533???????4540
4401???????4407???????4414???????4541????4547???????4554???????4613
4402???????4408???????4415???????4542????4548???????4555???????4614
4409???????4416???????????????4549???????4556???????4615
4410???????4417???????????????4550???????4557???????4616
4411???????4418???????????????4551???????4558???????4617
4,412 4,419 4,552 4559 Hes
4413???????4420???????????????4553???????4560???????4618.
4421???????4427???????4434???????4561????4567???????4574
4422???????4428???????4435???????4562????4568???????4575
4429???????4436???????????????4569???????4576
4430???????4437???????????????4570???????4577
4431???????4438???????????????4571???????4578
4432???????4439???????????????4572???????4579
4433???????4440???????????????4573???????4580
77. according to the compound of claim 1, described compound is selected from the end product compound of following examples:
3305????3478????3654????3834????3408.1????3588.1????3768.1????3966.1????4146????4323
3306????3479????3655????3835????3409.1????3589.1????3769.1????3967.1????4147????4324
3307????3480????3656????3836????3410.1????3590.1????3770.1????3968.1????4148????4325
3308????3481????3657????3837????3411.1????3591.1????3771.1????3969.1????4149????4326
3324????3497????3674????3854????3428.1????3608.1????3788.1????3986.1????4166????4343
3325????3498????3675????3855????3429.1????3609.1????3789.1????3987.1????4167????4344
3326????3499????3676????3856????3430.1????3610.1????3790.1????3988.1????4168????4345
3327????3500????3677????3857????3431.1????3611.1????3791.1????3989.1????4169????4346
3344????3517????3694????3874????3448.1????3628.1????3808.1????4006??????4186????4363
3345????3518????3695????3875????3449.1????3629.1????3809.1????4007??????4187????4364
3346????3519????3696????3876????3450.1????3630.1????3810.1????4008??????4188????4365
3347????3520????3697????3877????3451.1????3631.1????3811.1????4009??????4189????4366
3364????3535????3714????3893????3468.1????3648.1????3826.1????4026??????4206????4383
3365????3536????3715????3894????3469.1????3649.1????3827.1????4027??????4207????4384
3366????3537????3716????3895????3470.1????3650.1????3828.1????4028??????4208????4385
3367????3538????3717????3896????3471.1????3651.1????3829.1????4029??????4209????4386
3382
3383????3554????3734????3912????3488.1????3668.1????3846.1????4046??????4226????4403
3555????3735????3913????3489.1????3669.1????3847.1????4047??????4227????4404
3556????3736????3914????3490.1????3670.1????3848.1????4048??????4228????4405
3557????3737????3915????3491.1????3671.1????3849.1????4049??????4229????4406
3398????3574????3754????3931????3508.1????3688.1????3866.1????4066??????4246????4423
3399????3575????3755????????????3509.1????3689.1????3867.1????4067??????4247????4424
3400????3576????3756????????????3510.1????3690.1????3868.1????4068??????4248????4425
3401????3577????3757????????????3511.1????3691.1????3869.1????4069??????4249????4426
3708.1
3418????3594????3774????3948????3528.1????3709.1????3886.1????4086??????4266????4443
3419????3595????3775????3949????3529.1????3710.1????3887.1????4087??????4267????4444
3420????3596????3776????3950????3530.1????3711.1????3888.1????4088??????4268????4445
3421????3597????3777????3951????3531.1??????????????3889.1????4089??????4269????4446
3728.1
3438????3614????3794????3968????3548.1????3729.1????3906.1????4106??????4286????4463
3439????3615????3795????3969????3549.1????3730.1????3907.1????4107??????4287????4464
3440????3616????3796????3970????3550.1????3731.1????3908.1????4108??????4288????4465
3441????3617????3797????3971????3551.1??????????????3909.1????4109??????4289????4466
3458????3634????3814????3988????3568.1????3748.1????3946.1????4126??????4306????4483
3459????3635????3815????3989????3569.1????3749.1????3947.1????4127??????4307????4484
3460????3636????3816????3990????3570.1????3750.1????3948.1????4128??????4308????4485
3461????3637????3817????3991????3571.1????3751.1????3949.1????4129??????4309????4486
4503?????4563
4504?????4564
4505?????4565
4506?????4566
4523?????4583
4524?????4584
4525?????4585
4526?????4586
4543?????4603
4544?????4604
4545?????4605
4546 Hes
4606.
78. compound, described compound is selected from:
Figure A038047200065C1
Figure A038047200067C1
79. according to the compound of claim 1, described compound is selected from:
Figure A038047200070C1
With
80. compound, described compound is selected from:
Figure A038047200073C3
With
81. compound, described compound is selected from:
With
82. according to the compound of claim 1, described compound is selected from:
Figure A038047200074C2
With
83. according to the compound of claim 1, described compound is selected from:
Figure A038047200075C1
With
84. 3 compound according to Claim 8, wherein compound is selected from the compound of isomer 2.
85. according to the compound of claim 79, wherein compound is selected from the compound of isomer 2.
86. according to the compound of claim 1, described compound is selected from:
Figure A038047200077C1
With
87. according to the compound of claim 78, described compound is selected from:
Figure A038047200078C4
88. according to the compound of claim 1, its its be selected from
Figure A038047200079C1
With
89. 8 compound according to Claim 8, described compound has following formula:
Figure A038047200079C3
90. 8 compound according to Claim 8, described compound has following formula:
Figure A038047200079C4
91. according to the compound of claim 1, described compound is selected from:
With
Figure A038047200080C2
92. according to the compound of claim 1, described compound has following formula:
Figure A038047200080C3
93. according to the compound of claim 1, described compound has following formula:
Figure A038047200080C4
94. according to the compound of claim 1, described compound is selected from:
With
Figure A038047200081C2
95. according to the compound of claim 1, described compound has following formula:
96. according to the compound of claim 1, described compound has following formula:
Figure A038047200081C4
97. according to the compound of claim 1, described compound is selected from:
98. according to the compound of claim 1, described compound has following formula:
99. according to the compound of claim 1, described compound has following formula:
Figure A038047200082C3
100. pharmaceutical composition, its comprise significant quantity according to each compound and pharmaceutically acceptable carrier in the claim 1 to 99.
101. pharmaceutical composition, it comprises the compound and the pharmaceutically acceptable carrier according to claim 35 of significant quantity.
102. pharmaceutical composition, its comprise significant quantity according to each compound and pharmaceutically acceptable carrier in the claim 91 to 93.
103. in the purposes of preparation in the medicine, this medicine is to be used for according to each compound in the claim 1 to 99:
(A) in the patient of needs treatment, the treatment abnormal growth of cells; Or
(B) in the patient of needs treatment, the tumour of active ras oncogene is expressed in treatment; Or
(C) in the patient of needs treatment, treating wherein, Ras protein is the cancer that is activated owing to the sudden change of the carinogenicity in the gene beyond the Ras gene.
104. in the purposes of preparation in the medicine, this medicine is to treat cancer in the patient of needs treatment according to each compound in the claim 1 to 99.
105. according to each compound in the claim 1 to 99 in the purposes of preparation in the medicine, this medicine is to be used for the treatment of cancer in the patient of needs treatment, and wherein this cancer is selected from: carcinoma of the pancreas, lung cancer, myeloid leukemia, Tiroidina filter palpebral edema knurl, myelodysplastic syndrome, head and neck cancer, melanoma, mammary cancer, prostate cancer, ovarian cancer, bladder cancer, neurospongioma, epidermis cancer, colorectal carcinoma, non-Hodgkin lymphoma and multiple knurl.
106. in the purposes of preparation in the medicine, this medicine suppresses the ras farnesyl protein transferase in the patient of needs treatment according to each compound in the claim 1 to 99.
107. according to each compound in the claim 1 to 99 in the purposes of preparation in the medicine, this medicine is to be used for the treatment of cancer in the patient of needs treatments, and this treatment comprises simultaneously or in succession this medicine of co-administered significant quantity and at least a chemotherapeutic and/or the radiation of significant quantity to this patient.
108. according to the purposes of claim 107, wherein the cancer of being treated is a lung cancer, and:
(a) chemotherapeutic is selected from: carboplatin, safe element and taxotere; Or
(b) chemotherapeutic is selected from: gemcitabine and cis-platinum.
109. according to the purposes of claim 107, wherein chemotherapeutic is a taxol.
110. according to each compound in the claim 1 to 99 in the purposes of preparation in the medicine, this medicine is to be used for the treatment of cancer in the patient of needs treatment, and this treatment comprises this patient's while or co-administered in succession this medicine of significant quantity and at least a signal transduction inhibitor of significant quantity used.
111. according to the purposes of claim 110, wherein signal transduction inhibitor is selected from: Gleevec (imatinib mesylate), Iressa, OSI-774, Imclone C225, AbgenixABX-EGF and Herceptin (trastuzumab).
112. according to each compound in the claim 1 to 99 in the purposes of preparation in the medicine, this medicine is to be used for the treatment of cancer in the patient of needs treatment, this treatment comprises this medicament and at least two kinds of different antineoplastic agents of this patient being used significant quantity, and described antineoplastic agent is selected from:
(1) taxanes;
(2) iridium-platinum complex;
(3) EGF inhibitor, it is an antibody;
(4) EGF inhibitor, it is a small molecules;
(5) VEGF inhibitor, it is an antibody;
(6) VEGF kinase inhibitor, it is a small molecules;
(7) estrogen receptor antagon or selective estrogen receptor modulators;
(8) antitumor nucleoside derivates;
(9) Ai Boxi ketone (Epothilone);
(10) topology isomerase inhibitors;
(11) vinca alkaloids;
(12) antibody, it is that α V β 3 integrates plain inhibitor; With
(13) α V β 3 integrates plain micromolecular inhibitor;
(14) folate antagonist;
(15) ribonucleotide reductase inhibitor;
(16) anthracycline antibiotics;
(17) biological product;
(18) Thalidomide (or relevant imide); And
(19) Gleevec (imatinib mesylate).
113. according to the purposes of claim 112, wherein be to use two kinds of antineoplastic agents, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex.
114. according to the purposes of claim 113, wherein:
(a) this Taxan is a taxol, and this iridium-platinum complex is a carboplatin; Or
(b) this Taxan is a taxol, and this iridium-platinum complex is a cis-platinum; Or
(c) this Taxan is a docetaxel, and this iridium-platinum complex is a cis-platinum; Or
(d) this Taxan is a docetaxel, and this iridium-platinum complex is a carboplatin.
115. according to the purposes of claim 113, wherein:
(a) this Taxan is a taxol, with about 150 milligrams to being administered once in about 250 milligrams/square metre per three weeks in each cycle of amount, and this iridium-platinum complex is a carboplatin, is about 5 to about 8 be administered once in per three weeks in each cycle of amount so that AUC to be provided; Or
(b) this Taxan is a docetaxel, with about 50 milligrams to being administered once in about 100 milligrams/square metre per three weeks in each cycle of amount, and this iridium-platinum complex is a cis-platinum, with about 60 milligrams to being administered once in about 100 milligrams/square metre per three weeks in each cycle of amount.
116. the purposes of claim 115, wherein this medicine is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice.
117. according to each compound in the claim 78 to 99 in the purposes of preparation in the medicine, this medicine is to be used for the treatment of cancer in the patient of needs treatment, this treatment comprises this medicine and at least two kinds of different antineoplastic agents of this patient being used significant quantity, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex.
118. according in the claim 97 to 99 each compound the preparation medicine in purposes, this medicine is to be used for the treatment of cancer in the patient of needs treatment, this treatment comprises this medicine and at least two kinds of different antineoplastic agents of this patient being used significant quantity, wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is an iridium-platinum complex.
119., wherein be the treatment nonsmall-cell lung cancer according to the purposes of claim 113.
120. the purposes of claim 112 wherein is to use two kinds of antineoplastic agents:
(A) wherein a kind of antineoplastic agent is a Taxan, and another kind of antineoplastic agent is the EGF inhibitor, and this EGP inhibitor is an antibody; Or
(B) wherein a kind of antineoplastic agent is anti-nucleoside derivates, and another kind of antineoplastic agent is an iridium-platinum complex.
121. according to the purposes of claim 112, wherein be the treatment nonsmall-cell lung cancer, this treatment comprises the following material to significant quantity on this patient's administering therapeutic:
(a) this medicine; With
(b) carboplatin; And
(c) taxol.
122. according to the purposes of claim 121, wherein this medicine is one day administered twice, this carboplatin is to be administered once in per three weeks in each cycle, and this taxol is to be administered once in per three weeks in each cycle, this treatment be give in each cycle one to around.
123. method according to claim 122, wherein this medicine is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, this carboplatin is to be about 5 to about 8 be administered once in per three weeks in each cycle of amount so that AUC to be provided, this taxol is to be administered once with per three weeks in about 150 to each cycle of about 250 milligrams/square metre amount, and wherein this carboplatin and taxol are in administration on the same day.
124. according to the purposes of claim 112, wherein be the treatment nonsmall-cell lung cancer, this treatment comprises the following material to significant quantity on this patient's administering therapeutic:
(A) this medicine and cis-platinum and gemcitabine; Or
(B) this medicine and carboplatin and gemcitabine.
125. purposes according to claim 124, wherein in (A), this medicine is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, this cis-platinum is to each cycle of about 100 milligrams/square metre amount per three or be administered once all around with about 60, reaching this gemcitabine is to be administered once with about 750 to each one week of cycle of about 1250 milligrams/square metre amount, and this treatment is weekly to give for one to seven week the phase; And in (B), this medicine is with about 50 milligrams of extremely about 200 milligrams amount one day administered twice, this carboplatin is to be about 5 to about 8 be administered once in per three weeks in each cycle of amount so that AUC to be provided, reaching this gemcitabine is to be administered once with about 750 to each one week of cycle of about 1250 milligrams/square metre amount, and this treatment is to give for one to seven week each cycle.
126. according to each compound in the claim 1 to 99 in the purposes of preparation in the medicine, this medicine is to be used for the treatment of cancer in the patient of needs treatment, this treatment comprises that described antineoplastic agent is selected to this medicine and the antineoplastic agent of significant quantity on this patient's administering therapeutic:
(1) EGF inhibitor, it is an antibody;
(2) EGF inhibitor, it is a small molecules;
(3) VEGF inhibitor, it is an antibody; Or
(4) VEGF kinase inhibitor, it is a small molecules.
127. according to the method for claim 126, wherein this antineoplastic agent is selected from: Herceptin (trastuzumab), Cetuximab (Cetuximab), Tarceva, Iressa, rhuMAb-VEGF, IMC-1C11, SU5416 or SU6688.
128. according to the purposes of claim 113, wherein:
(A) this Taxan is a taxol, with about 150 milligrams to being administered once in about 250 milligrams/square metre each one week of cycle of amount, and this iridium-platinum complex is a carboplatin, is about 5 to about 8 be administered once in each one week of cycle of amount so that AUC to be provided; Or
(B) this Taxan is a docetaxel, with about 50 milligrams to being administered once in about 100 milligrams/square metre each one week of cycle of amount, and this iridium-platinum complex is a cis-platinum, with about 60 milligrams to being administered once in about 100 milligrams/square metre each one week of cycle of amount.
129. according to the purposes of claim 107, wherein the cancer of being treated is the squamous cell carcinoma of head and neck, and this treatment comprises the following material of significant quantity on the administering therapeutic:
(A) (1) this medicine, with (2) one or more antineoplastic agent, described antineoplastic agent is selected from: (a) taxanes and (b) iridium-platinum complex; Or
(B) (1) this medicine, with (2) at least two kinds of different antineoplastic agents, described antineoplastic agent is selected from: (a) taxanes; (b) iridium-platinum complex; Reach (c) antitumor nucleoside derivates.
130. according to the purposes of claim 107, wherein the cancer of being treated is CML, and this treatment comprises the following material of significant quantity on the administering therapeutic:
(A) this medicine, Gleevec (imatinib mesylate) and Interferon, rabbit; Or
(B) this medicine, Gleevec (imatinib mesylate) and by the Interferon, rabbit of PEGization.
131. according to the purposes of claim 107, wherein the cancer of being treated is AML, and this treatment comprises the following material of significant quantity on the administering therapeutic:
(A) this medicine and antitumor nucleoside derivates; Or
(B) this medicine, antitumor nucleoside derivates and anthracycline antibiotics.
132. according to the method for claim 107, wherein the cancer of being treated is a non-Hodgkin lymphoma, and this treatment comprises the following material of significant quantity on the administering therapeutic:
(A) this medicine and Rituximab (Rituximab); Or
(B) this medicine, Rituximab (Rituximab) and antitumor nucleoside derivates; Or
(C) this medicine and Genasense.
133. according to the purposes of claim 107, wherein the cancer of being treated is a multiple myeloma, and this treatment comprises the following material of significant quantity on the administering therapeutic:
(A) this medicine and proteoplast inhibitor; Or
(B) this medicine and Thalidomide or relevant imide; Or
(C) this medicine and Thalidomide.
134. according to each purposes in the claim 102 to 133, the compound that wherein is used to prepare this medicine is the compound according to claim 35.
135. according to each purposes in the claim 102 to 133, the compound that wherein is used for preparing this medicine is for according to each compound of claim 97 to 99.
136. following formula: compound:
Or its pharmacy acceptable salt or solvate, wherein:
Expression N or N one of among a, b, c and the d +O -, and all the other a, b, c and d group are represented carbon, wherein each carbon has the R that is combined on this carbon 1Or R 2Group; Or
Each a, b, c and d are carbon, and wherein each carbon has the R that is combined on this carbon 1Or R 2Group;
Dotted line (---) the optional key of expression;
When this optional key did not exist, X represented N or CH, and when this optional key existed, X represented C;
When key optional between carbon atom 5 and the carbon atom 6, then have only an A substituting group to be combined on the C-5, and have only a B substituting group to be combined on the C-6, and A or B are not H;
When not having optional key between carbon atom 5 and the carbon atom 6, then there are two substituting groups to be combined on the C-5, wherein each A substituting group is independent the selection, and there are two B substituting groups to be combined on the C-6, wherein each B substituting group is independent the selection, and wherein have at least in two A substituting groups to have at least to be a H in one or two B substituting group, and wherein have at least in two A substituting groups and have at least not to be a H in one or two B substituting group;
A and B are independently selected from:
(1)-H；
(2)-R 9；
(3)-R 9-C(O)-R 9；
(4)-R 9-CO 2-R 9a；
(5)-(CH 2) pR 26；
(6)-C (O) N (R 9) 2, each R wherein 9Identical or different;
(7)-C(O)NHR 9；
(8)-C(O)NH-CH 2-C(O)-NH 2；
(9)-C(O)NHR 26；
(10)-(CH 2) pC(R 9)-O-R 9a；
(11)-(CH 2) p(R 9) 2, each R wherein 9Identical or different;
(12)-(CH 2) pC(O)R 9；
(13)-(CH 2) pC(O)R 27a；
(14)-(CH 2) pC (O) N (R 9) 2, each R wherein 9Identical or different;
(15)-(CH 2) pC(O)NH(R 9)；
(16)-(CH 2) pC (O) N (R 26) 2, each R wherein 26Identical or different;
(17)-(CH 2) pN(R 9)-R 9a；
(18)-(CH 2) pN (R 26) 2, R wherein 26Identical or different;
(19)-(CH 2) pNHC(O)R 50；
(20)-(CH 2) pNHC(O) 2R 50；
(21)-(CH 2) pN (C (O) R 27a) 2, each R wherein 27aIdentical or different;
(22)-(CH 2) pNR 51C(O)R 27；
(23)-(CH 2) pNR 51C (O) R 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(24)-(CH 2) pNR 51C(O)NR 27；
(25)-(CH 2) pNR 51C (O) NR 27, R wherein 51Be not H, and R 51With R 27Form 5 or 6 yuan of heterocycloalkyl rings together with their institute's bonded atoms;
(26)-(CH 2) pNR 51C (O) N (R 27a) 2, each R wherein 27aIdentical or different;
(27)-(CH 2) pNHSO 2N (R 51) 2, each R wherein 51Identical or different;
(28)-(CH 2) pNHCO 2R 50；
(29)-(CH 2) pNC(O)NHR 51；
(30)-(CH 2) pCO 2R 51；
(31)-NHR 9；
(32)
Figure A038047200090C1
R wherein 30With R 31Identical or different, and each p is independent the selection; Its condition is for each following group
Work as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl and aralkyl;
(33)
Figure A038047200090C3
R wherein 30, R 31, R 32And R 33Identical or different; Its condition is to work as R 30Or R 31In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 30Or R 31Be selected from: H, alkyl, aryl and aralkyl; And its condition is to work as R 32Or R 33In one of be selected from :-OH ,=O ,-OR 9a,-NH 2,-NHR 9a,-N (R 9a) 2,-N 3,-NHR 9bAnd-N (R 9a) R 9bThe time, all the other R then 32Or R 33Be selected from: H, alkyl, aryl and aralkyl;
(34)-thiazolinyl-CO 2R 9a
(35)-thiazolinyl-C (O) R 9a
(36)-thiazolinyl-CO 2R 51
(37)-thiazolinyl-C (O)-R 27a
(38) (CH 2) p-thiazolinyl-CO 2-R 51
(39)-(CH 2) pC=NOR 51And
(40)-(CH 2) p-phthalic imidine;
P is 0,1,2,3 or 4;
Each R 1With R 2Be independently selected from:
(1)H；
(2) halogen;
(3)-CF 3；
(4)-OR 10；
(5)-COR 10；
(6)-SR 10；
(7)-S (O) tR 15, wherein t is 0,1 or 2;
(8)-N(R 10) 2；
(9)-NO 2；
(10)-OC(O)R 10；
(11)-CO 2R 10；
(12)-OCO 2R 15；
(13)-CN；
(14)-NR 10COOR 15；
(15)-SR 15C(O)OR 15；
(16)-SR 15N (R 13) 2, its condition is-SR 15N (R 13) 2In R 15Be not
-CH 2, and each R wherein 13Be independently selected from: H and-C (O) OR 15
(17) benzotriazole-1-base oxygen base;
(18) tetrazolium-5-base sulfenyl;
(19) substituted tetrazolium-5-base sulfenyl;
(20) alkynyl;
(21) thiazolinyl; And
(22) alkyl, this alkyl or alkenyl optional by halogen ,-OR 10Or-CO 2R 10Replace;
R 3With R 4Identical or different, and each represents H and R independently 1With R 2Any substituting group;
R 5, R 6, R 7And R 7aEach is expression independently: H ,-CF 3,-COR 10, alkyl or aryl, this alkyl or aryl is chosen quilt-S (O) wantonly tR 15,-NR 10COOR 15,-C (O) R 10Or-CO 2R 10Replace, or R 5With R 6Together expression=O or=S;
R 8Be selected from:
H, With
Figure A038047200092C2
R 9Be selected from:
(1) unsubstituted heteroaryl;
(2) substituted heteroaryl;
(3) alkoxy aryl;
(4) substituted alkoxy aryl;
(5) Heterocyclylalkyl;
(6) substituted Heterocyclylalkyl;
(7) Heterocyclylalkyl alkyl;
(8) substituted Heterocyclylalkyl alkyl;
(9) unsubstituted heteroaralkyl;
(10) substituted heteroaralkyl;
(11) unsubstituted heteroaryl thiazolinyl;
(12) substituted heteroaryl thiazolinyl;
(13) unsubstituted heteroaryl alkynyl; And
(14) substituted heteroaryl alkynyl; This substituted R wherein 9Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CO 2R 14；
(3)-CH 2OR 14；
(4) halogen;
(5) alkyl;
(6) amino;
(7) trityl;
(8) Heterocyclylalkyl;
(9) cycloalkyl;
(10) aralkyl;
(11) heteroaryl;
(12) heteroaralkyl, and
(13)
Figure A038047200093C1
R wherein 14Be independently selected from: H; Alkyl; Aryl, aralkyl, heteroaryl and heteroaralkyl;
R 9aBe selected from: alkyl and aralkyl;
R 9bBe selected from:
(1)-C(O)R 9a；
(2)-SO 2R 9a；
(3)-C(O)NHR 9a；
(4)-C (O) OR 9aAnd
(5)-C(O)N(R 9c) 2；
Each R 9cBe independently selected from: H, alkyl and aralkyl;
R 10Be selected from: H; Alkyl; Aryl and aralkyl;
R 11Be selected from:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) Heterocyclylalkyl; And
(10) substituted Heterocyclylalkyl;
Wherein this substituted alkyl, substituted cycloalkyl and substituted Heterocyclylalkyl R 11Group is replaced by one or more substituting group, and described substituting group is selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) fluorine; And
(3) alkyl; And
Wherein this substituted aryl and substituted heteroaryl R 11Group is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2) halogen; And
(3) alkyl;
R 11aBe selected from:
(1)H；
(2)OH；
(3) alkyl;
(4) substituted alkyl;
(5) aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) Heterocyclylalkyl;
(12) substituted Heterocyclylalkyl; And
(13)-OR 9a；
Wherein this substituted alkyl, substituted cycloalkyl and substituted Heterocyclylalkyl R 11aGroup is replaced by one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined in (meaning promptly has only one-OH group can be combined on the carbon atom) on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) fluorine;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl, and
(11) assorted thiazolinyl; And
Wherein this substituted aryl and substituted heteroaryl R 11aGroup has one or more substituting group, and described substituting group is independently selected from:
(1)-and OH, its condition is when surpassing one-OH group, then respectively-the OH group is to be combined on the different carbon atoms;
(2)-CN；
(3)-CF 3；
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) Heterocyclylalkyl;
(8) aralkyl;
(9) heteroaralkyl;
(10) thiazolinyl; And
(11) assorted thiazolinyl;
R 12Be selected from: H, alkyl, piperidine ring V, cycloalkyl reach-alkyl-(piperidine ring V);
R 15Be selected from: alkyl and aryl;
R 21, R 22And R 46Be independently selected from:
(1)-H；
(2) alkyl;
(3) unsubstituted aryl;
(4) be substituted aryl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(5) unsubstituted cycloalkyl;
(6) be substituted cycloalkyl by what one or more substituting group replaced, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(7) following formula heteroaryl,
Figure A038047200096C1
With
Figure A038047200096C2
(8) following formula Heterocyclylalkyl:
Figure A038047200096C3
R wherein 44Be selected from:
(a)-H；
(b) alkyl;
(c) alkyl carbonyl;
(d) carbalkoxy;
(e) haloalkyl; And
(f)-C(O)NH(R 51)；
(9)-NH 2, its condition is R 21, R 22And R 46In have only one to can be-NH 2, and its condition is to work as R 21, R 22And R 46In one of be-NH 2The time, then all the other groups are not-OH;
(10)-and OH, its condition is R 21, R 22And R 46In have only one to can be-OH, and its condition is to work as R 21, R 22And R 46In one of be-during OH, then all the other groups are not-NH 2And
(11) alkyl that is replaced by one or more substituting group, described substituting group is selected from :-OH and-NH 2, and its condition is to have only one-OH or one-NH on substituted carbon 2Group; Or
(12) R 21With R 22Form cyclic rings together with their institute's bonded carbon, described ring is selected from:
(a) unsubstituted cycloalkyl;
(b) cycloalkyl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(c) unsubstituted cycloalkenyl group;
(d) cycloalkenyl group that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen, CF 3And OH;
(e) Heterocyclylalkyl;
(f) unsubstituted aryl;
(g) aryl that is replaced by one or more substituting group, described substituting group is independently selected from: alkyl, halogen ,-CN ,-CF 3,-OH and alkoxyl group; And
(i) heteroaryl, described heteroaryl is selected from:
With
Figure A038047200097C2
R 26Be selected from:
(1)-H；
(2) alkyl;
(3) alkoxyl group;
(4)-CH 2-CN；
(5)R 9；
(6)-CH 2CO 2H；
(7)-C (O) alkyl; And
(8) CH 2CO 2Alkyl;
R 27Be selected from:
(1)-H；
(2)-OH；
(3) alkyl; And
(4) alkoxyl group;
R 27aBe selected from:
(1) alkyl; With
(2) alkoxyl group;
R 30, R 31, R 32And R 33Be independently selected from:
(1)-H；
(2)-OH；
(3)＝O；
(4) alkyl;
(5) aryl;
(6) aralkyl;
(7)-OR 9a；
(8)-NH 2；
(9)-NHR 9a；
(10)-N (R 9a) 2, each R wherein 9aBe independent the selection;
(11)-N 3；
(12)-NHR 9bAnd
(13)-N(R 9a)R 9b；
R 50Be selected from:
(1) alkyl;
(2) unsubstituted heteroaryl;
(3) substituted heteroaryl; And
(4) amino;
Wherein be substituted R at this 50Substituting group on the group is independently selected from: alkyl; Halogen; And-OH;
R 51Be selected from: H and alkyl; And
Its condition is that in substituted Heterocyclylalkyl part, the ring carbon atom adjacent with ring hetero atom do not replaced by heteroatoms or halogen atom; And
Its condition is that in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not exceeded a heteroatoms and replaces; And
Its condition is that in substituted Heterocyclylalkyl part, not adjacent with ring hetero atom ring carbon atom is not replaced by heteroatoms and halogen atom; And
Its condition is that the ring carbon in being substituted cycloalkyl moiety is not exceeded a heteroatoms and replaces; And
Its condition is that the carbon atom in being substituted moieties is not exceeded a heteroatoms and replaces; And
Its condition is, the same carbon atom in being substituted moieties had not only replaced by heteroatoms but also by halogen atom.
CNB038047209A 2002-02-27 2003-02-25 Farnesyl protein transferase inhibitors as antitumor agents Expired - Fee Related CN100537542C (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10/085,896 2002-02-27
US10/085,896 US20030229099A1 (en) 2000-08-30 2002-02-27 Novel farnesyl protein transferase inhibitors as antitumor agents
US10/325,896 US7342016B2 (en) 2000-08-30 2002-12-19 Farnesyl protein transferase inhibitors as antitumor agents
US10/325,896 2002-12-19

Publications (2)

Publication Number Publication Date
CN1630641A true CN1630641A (en) 2005-06-22
CN100537542C CN100537542C (en) 2009-09-09

Family

ID=27767345

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB038047209A Expired - Fee Related CN100537542C (en) 2002-02-27 2003-02-25 Farnesyl protein transferase inhibitors as antitumor agents

Country Status (19)

Country Link
US (1) US7342016B2 (en)
EP (1) EP1492772A1 (en)
JP (1) JP2005525356A (en)
KR (1) KR20040098004A (en)
CN (1) CN100537542C (en)
AR (1) AR039557A1 (en)
AU (1) AU2003215389B2 (en)
BR (1) BR0308071A (en)
CA (1) CA2477328A1 (en)
CO (1) CO5611194A2 (en)
IL (1) IL163673A0 (en)
MX (1) MXPA04008303A (en)
NO (1) NO20044053L (en)
NZ (1) NZ534809A (en)
PE (1) PE20031038A1 (en)
PL (1) PL372335A1 (en)
RU (1) RU2004128465A (en)
TW (1) TW200303867A (en)
WO (1) WO2003072549A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777646A (en) * 2016-04-08 2016-07-20 西南科技大学 Novel preparation method of 5-iodine-2-phenyl-1-methyl imidazole
CN111454329A (en) * 2020-04-07 2020-07-28 哈尔滨师范大学 Isoindolinone bridged cyclic nonapeptide with anticancer activity and preparation method thereof
CN115385892A (en) * 2021-10-28 2022-11-25 天津市昕晨投资发展有限公司 Desloratadine derivative, preparation method and application thereof

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RS20181002A1 (en) * 2003-05-30 2018-12-31 Genentech Inc Treatment with anti-vegf antibodies
TW200510384A (en) * 2003-08-07 2005-03-16 Schering Corp Novel farnesyl protein transferase inhibitors as antitumor agents
KR20070034524A (en) * 2004-05-28 2007-03-28 버텍스 파마슈티칼스 인코포레이티드 Muscarinic receptor modulators
CA2569887A1 (en) 2004-06-09 2005-12-22 Glaxo Group Limited Pyrrolopyridine derivatives
CN101128202A (en) 2004-12-14 2008-02-20 先灵公司 Farnesyl protein transferase inhibitors and methods for treating proliferative diseases
CA2591705A1 (en) * 2004-12-21 2006-06-29 Schering Corporation Novel farnesyl protein transferase inhibitors as antitumor agents
JP2009523799A (en) * 2006-01-19 2009-06-25 シェーリング コーポレイション Piperazine derivatives as farnesyl protein transferase inhibitors
WO2008054598A2 (en) * 2006-09-29 2008-05-08 Schering Corporation Panel of biomarkers for prediction of fti efficacy
MX2009006779A (en) * 2006-12-19 2009-08-27 Genentech Inc Vegf-specific antagonists for adjuvant and neoadjuvant therapy and the treatment of early stage tumors.
EP2313091A4 (en) * 2008-07-14 2012-04-04 Univ Kingston Pharmaceutical compositions comprising ret inhibitors and methods for the treatment of cancer
JP2012520884A (en) 2009-03-18 2012-09-10 ザ ボード オブ トラスティーズ オブ ザ リランド スタンフォード ジュニア ユニバーシティー Methods and compositions for treating flaviviridae viral infections
US9227962B2 (en) 2013-03-13 2016-01-05 Boston Biomedical, Inc. Heterocyclic substituted-3-heteroarylidenyl-2-indolinone derivative
US9187454B2 (en) * 2013-03-13 2015-11-17 Boston Biomedical, Inc. Inhibitors of kinases and cancer stem cells, and methods of preparation and use thereof

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5089496A (en) * 1986-10-31 1992-02-18 Schering Corporation Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies
US4826853A (en) 1986-10-31 1989-05-02 Schering Corporation 6,11-Dihydro-11-(N-substituted-4-piperidylidene)-5H-benzo(5,6)cyclohepta(1,2-B)pyridines and compositions and methods of use
US5393890A (en) * 1988-06-02 1995-02-28 Ajinomoto Co., Inc. Piperidine derivatives and hypotensives containing the same
JPH05506249A (en) * 1990-10-10 1993-09-16 シェリング・コーポレーション Bisbenzocycloheptapiperidylidene, piperidine and piperazine compounds, compositions and uses
GB9513371D0 (en) 1995-06-30 1995-09-06 Biocine Spa Immunogenic detoxified mutant toxins
US5643909A (en) 1993-04-19 1997-07-01 Syntex (U.S.A.) Inc. 10,11-Methanodibenzosuberane derivatives
US5721236A (en) * 1993-10-15 1998-02-24 Schering Corporation Tricyclic carbamate compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
US6075025A (en) * 1993-10-15 2000-06-13 Schering Corporation Tricyclic carbamate compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
IL111235A (en) * 1993-10-15 2001-03-19 Schering Plough Corp Pharmaceutical compositions for inhibition of g-protein function and for treatment of proliferative diseases containing tricyclic compounds some such compounds and process for preparing part of them
US5719148A (en) * 1993-10-15 1998-02-17 Schering Corporation Tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
US5874442A (en) * 1995-12-22 1999-02-23 Schering-Plough Corporation Tricyclic amides useful for inhibition of G-protein function and for treatment of proliferative disease
TW350844B (en) * 1995-12-22 1999-01-21 Schering Corp Tricyclic amides useful to inhibition of G-protein function and for treatment of proliferative diseases
US5861395A (en) * 1996-09-13 1999-01-19 Schering Corporation Compounds useful for inhibition of farnesyl proteins transferase
US6071907A (en) * 1996-09-13 2000-06-06 Schering Corporation Tricyclic compounds useful as FPT inhibitors
WO1998011092A1 (en) 1996-09-13 1998-03-19 Schering Corporation Tricyclic antitumor compounds being farnesyl protein transferase inhibitors
CN1237176A (en) * 1996-09-13 1999-12-01 先灵公司 Tricyclic compounds useful as FPT inhibitors
GB9801231D0 (en) * 1997-06-05 1998-03-18 Merck & Co Inc A method of treating cancer
BR9811470A (en) 1997-06-17 2000-09-19 Schering Corp Derivatives of benzo (5,6) cyclohepta (1,2-b) pyridine for the inhibition of farnesyl protein transferase.
DE69825589T2 (en) 1997-06-17 2005-09-08 Schering Corp. BENZPYRIDO CYCLOHEPTAN DERIVATIVES WITH FARNESYL PROTEIN TRANSFERASE INHIBIVING EFFECT
ZA985205B (en) 1997-06-17 1998-12-15 Schering Corp Novel n-substituted urea inhibitors of arnesyl-protein transferase
IL133393A0 (en) 1997-06-17 2001-04-30 Schering Corp Novel tricyclic sulfonamide inhibitors of farnesyl-protein transferase
US5925648A (en) * 1997-07-29 1999-07-20 Schering Corporation Tricyclic N-cyanoimines useful as inhibitors of a farnesyl-protein transferase
IL143409A0 (en) 1998-12-18 2002-04-21 Schering Corp Farnesyl protein transferase inhibitors
TR200101755T2 (en) 1998-12-18 2001-09-21 Schering Corporation Tricyclic farnesyl protein transferase inhibitors.
AU2292801A (en) * 1999-12-22 2001-07-03 Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The Compositions and methods for treatment of breast cancer
DK1255537T3 (en) 2000-02-04 2006-08-21 Janssen Pharmaceutica Nv Farnesyl protein transferase inhibitors for the treatment of breast cancer
AR033680A1 (en) * 2000-08-30 2004-01-07 Schering Corp USEFUL TRICICLIC COMPOUNDS AS INHIBITORS OF FARNESIL PROTEINO TRANSFERASA AND ITS USE FOR THE MANUFACTURE OF MEDICINES AS ANTITUMOR AGENTS
CA2468996A1 (en) * 2001-12-03 2003-06-12 Schering Corporation Use of fpt inhibitors and at least two antineoplastic agents in the treatment of cancer
TW200510384A (en) * 2003-08-07 2005-03-16 Schering Corp Novel farnesyl protein transferase inhibitors as antitumor agents

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777646A (en) * 2016-04-08 2016-07-20 西南科技大学 Novel preparation method of 5-iodine-2-phenyl-1-methyl imidazole
CN111454329A (en) * 2020-04-07 2020-07-28 哈尔滨师范大学 Isoindolinone bridged cyclic nonapeptide with anticancer activity and preparation method thereof
CN115385892A (en) * 2021-10-28 2022-11-25 天津市昕晨投资发展有限公司 Desloratadine derivative, preparation method and application thereof

Also Published As

Publication number Publication date
AU2003215389B2 (en) 2007-10-18
NO20044053L (en) 2004-11-26
AR039557A1 (en) 2005-02-23
MXPA04008303A (en) 2005-11-23
JP2005525356A (en) 2005-08-25
IL163673A0 (en) 2005-12-18
CO5611194A2 (en) 2006-02-28
RU2004128465A (en) 2005-09-27
US7342016B2 (en) 2008-03-11
BR0308071A (en) 2004-12-21
AU2003215389A1 (en) 2003-09-09
TW200303867A (en) 2003-09-16
NZ534809A (en) 2007-12-21
US20040122018A1 (en) 2004-06-24
PE20031038A1 (en) 2004-01-10
PL372335A1 (en) 2005-07-11
EP1492772A1 (en) 2005-01-05
CN100537542C (en) 2009-09-09
KR20040098004A (en) 2004-11-18
WO2003072549A1 (en) 2003-09-04
CA2477328A1 (en) 2003-09-04

Similar Documents

Publication Publication Date Title
CN1630641A (en) Farnesyl protein transferase inhibitors as antitumor agents
CN1081635C (en) Substituted pyrrolidin-3-Yl-alkyl-piperidines useful as tachykinin antagonists
CN1144791C (en) Triazole compounds and use thereof as dopamine-D3-ligands
CN1036394C (en) Carbostyril derivatives
CN1021223C (en) Process for 5-lipoxygense inhibiting 4-(4-phenyl-1-pip-erazing 1) phenols
CN1630657A (en) Deazapurines and uses thereof
CN1313450C (en) Tachykinin receptor antagonists
CN1288464A (en) 4-(2-keto-1-benzimidazolynyl) pipeidine compounds as ORL-1 receptor
CN1642912A (en) Sulfonylamino-derivatives as novel inhibitors of histone deacetylase
CN1681508A (en) Novel inhibitors of kinases
CN1642931A (en) Sulfonylamino-derivatives as novel inhibitors of histone deacetylase
CN1642915A (en) Benzamide derivatives useful as histone deacetylase inhibitors
CN1934091A (en) Imidazole compounds for the treatment of neurodegenerative disorders
CN101048406A (en) Novel substituted imidazole derivatives
CN1074413C (en) Novel benzimidazole derivatives having CGMP-phosphodisterase inhibiting activity
CN1976916A (en) Selected CGRP - antagonists, process for preparing them and their use as pharmaceutical compositions
CN1349990A (en) Heterocyclic compound, its preparation and use
CN1432015A (en) Indazoles substituted with 1,1-dioxoisothiazolidine useful as inhibitors of cell proliferation
CN1067655A (en) The fluorinated alkoxy-amino-benzyl derivative of nitrogen heterocyclic ring compounds
CN1434805A (en) Selective neurokinin antagonists
CN1092771A (en) The non-aromatic heterocycles that aminomethylene replaces
CN1281604C (en) Substituted pyrazole compounds
CN101048393A (en) Substituted N-arylsulfonylheterocyclic amines as gamma-secretase inhibitors
CN1503673A (en) antiinflammation agents
CN1849122A (en) Method of treating cancer using fpt inhibitors and at least two antineoplastic agents

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
ASS Succession or assignment of patent right

Owner name: PHARMECPIA DRUG R & D CO., LTD.

Free format text: FORMER OWNER: PHARMACOPEIA INC.

Effective date: 20050624

C41 Transfer of patent application or patent right or utility model
TA01 Transfer of patent application right

Effective date of registration: 20050624

Address after: American New Jersey

Applicant after: SCHERING CORP (US)

Co-applicant after: Pharmacopeia Drug Discovery

Address before: American New Jersey

Applicant before: SCHERING CORP (US)

Co-applicant before: Pharmacopeia Inc.

C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20090909

Termination date: 20120225